Nitrate ammonification by Nautilia profundicola AmH: experimental evidence consistent with a free hydroxylamine intermediate.
The process of nitrate reduction via nitrite controls the fate and bioavailability of mineral nitrogen within ecosystems; i.e., whether it is retained as ammonium (ammonification) or lost as nitrous oxide or dinitrogen (denitrification). Here, we present experimental evidence for a novel pathway of microbial nitrate reduction, the reverse hydroxylamine:ubiquinone reductase module (reverse-HURM) pathway. Instead of a classical ammonia-forming nitrite reductase that performs a 6 electron-transfer process, the pathway is thought to employ two catalytic redox modules operating in sequence: the reverse-HURM reducing nitrite to hydroxylamine followed by a hydroxylamine reductase that converts hydroxylamine to ammonium. Experiments were performed on Nautilia profundicola strain AmH, whose genome sequence led to the reverse-HURM pathway proposal. N. profundicola produced ammonium from nitrate, which was assimilated into biomass. Furthermore, genes encoding the catalysts of the reverse-HURM pathway were preferentially expressed during growth of N. profundicola on nitrate as an electron acceptor relative to cultures grown on polysulfide as an electron acceptor. Finally, nitrate-grown cells of N. profundicola were able to rapidly and stoichiometrically convert high concentrations of hydroxylamine to ammonium in resting cell assays. These experiments are consistent with the reverse-HURM pathway and a free hydroxylamine intermediate, but could not definitively exclude direct nitrite reduction to ammonium by the reverse-HURM with hydroxylamine as an off-pathway product. N. profundicola and related organisms are models for a new pathway of nitrate ammonification that may have global impact due to the wide distribution of these organisms in hypoxic environments and symbiotic or pathogenic associations with animal hosts.


[Use of Digital Health Records and "WebMovil" corporate service in the communication management of critical results of Microbiology, in the context of a primary health care area].
The objective was to describe and evaluate a new communication protocol of reporting critical results applied to Microbiology in a health area of Andalusia. The size and type of the critical values of Microbiology are analyzed for primary care patients. A new computerized reporting system was analyzed, in real time, through Diraya Digital Health Records, which integrates the analytical test module (MPA). The protocol is complemented, in collaboration with the Information Technology (IT), with the Junta de Andalucía short message service (SMS) "WebMovil". The total number of notices of critical results by the new protocol in 2012 was 817. The number of critical values for primary care was 570, of which 90 were for Microbiology. The most frequent notice was by isolation in the stool culture (n = 51; 56.67%). The prevalence of the critical values of Microbiology in primary care was 0.45/100. The average time of notifications was 13 minutes. The success rate of notifications was 97.7% and 0% obtained in the number of withdrawals. In 99.93% of cases the contact with the patient was stated and in 98.55% the medical intervention was also confirmed. Communication by a computerized system linked to the SMS technology showed a reduction in the time of notification, and produced additional benefits, such as eliminating the risk of error when there is no repetition of information from the recipient received by the laboratory. Furthermore, the use of SMS messages ensures that doctors on duty always receive information immediately.


SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.
The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.


Ischemic lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage.
To evaluate the associations among diffusion-weighted imaging (DWI) lesions, blood pressure (BP) dysregulation, MRI markers of small vessel disease, and poor outcome in a large, prospective study of primary intracerebral hemorrhage (ICH). The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a multicenter, observational study of ICH among white, black, and Hispanic patients. Of 600 patients, mean (±SD) age was 60.8 ± 13.6 years, median (interquartile range) ICH volume was 9.1 mL (3.5-20.8), and 79.6% had hypertension. Overall, 26.5% of cases had DWI lesions, and this frequency differed by race/ethnicity (black 33.8%, Hispanic 24.9%, white 20.2%, overall p = 0.006). A logistic regression model of variables associated with DWI lesions included lower age (odds ratio [OR] 0.721, p = 0.002), higher first recorded systolic BP (10-unit OR 1.12, p = 0.002), greater change in mean arterial pressure (MAP) prior to the MRI (10-unit OR 1.10, p = 0.037), microbleeds (OR 1.99, p = 0.008), and higher white matter hyperintensity (WMH) score (1-unit OR 1.16, p = 0.002) after controlling for race/ethnicity, leukocyte count, and acute in-hospital antihypertensive treatment. A second model of variables associated with poor 90-day functional outcome (modified Rankin Scale scores 4-6) included DWI lesion count (OR 1.085, p = 0.034) as well as age, ICH volume, intraventricular hemorrhage, Glasgow Coma Scale score, WMH score, race/ethnicity, acute in-hospital antihypertensive treatment, and ICH location. These results support the hypotheses that acute BP dysregulation is associated with the development of DWI lesions in primary ICH and that DWI lesions are, in turn, associated with poor outcomes.


Improved Childhood Diarrhea Treatment Practices in Ghana: A Pre-Post Evaluation of a Comprehensive Private-Sector Program.
Diarrhea is the fourth leading cause of child mortality in Ghana. In 2010, Ghana endorsed guidelines from the World Health Organization and the United Nations Children's Fund for use of zinc with low-osmolarity oral rehydration salts (ORS) for the treatment of acute childhood diarrhea. From late 2011 through 2014, the Strengthening Health Outcomes through the Private Sector (SHOPS) project implemented a comprehensive program in 3 regions of Ghana to increase the availability and use of ORS and zinc and to decrease incorrect use of antibiotics and antidiarrheals. The program included (1) partnering with local pharmaceutical firms to introduce and market locally produced zinc products, (2) collaborating with the Ghanaian Pharmacy Council to provide training and supportive supervision of private-sector providers on diarrhea management, and (3) conducting mass media campaigns to raise caregiver awareness. We evaluated the effect of this program using a baseline survey of 754 caregivers of children under 5 with diarrhea at the start of the intervention in 2012 and a follow-up survey of 751 caregivers in 2014. Regression analysis showed that use of ORS with zinc increased from 0.8% in 2012 to 29.2% in 2014 (P<.001), and antibiotic use declined from 66.2% to 38.2% (P<.001) during the same period. The magnitude and statistical significance of these results remained the same after including potential confounding factors as covariates. Inappropriate antibiotic use, however, remained high at follow-up. We conclude that similar programs applied in other settings have the potential to rapidly scale up use of ORS and zinc. Additional efforts are required to reduce persistent incorrect antibiotic use.


Presence of genes encoding the panton-valentine leukocidin exotoxin is not the primary determinant of outcome in patients with complicated skin and skin structure infections due to methicillin-resistant Staphylococcus aureus: results of a multinational trial.
The role of Panton-Valentine leukocidin (PVL) in determining the severity and outcome of complicated skin and skin structure infections (cSSSI) caused by methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) is controversial. We evaluated potential associations between clinical outcome and PVL status by using MRSA isolates from patients enrolled in two large, multinational phase three clinical trials assessing telavancin for the treatment of cSSSI (the ATLAS program). MRSA isolates from microbiologically evaluable patients were genotyped by pulsed-field gel electrophoresis (PFGE) and PCR for pvl and 31 other putative virulence determinants. A single baseline pathogen of MRSA was isolated from 522 microbiologically evaluable patients (25.1%) among 2,079 randomized patients. Of these MRSA isolates, 83.2% (432/519) exhibited the USA300 PFGE genotype and 89.1% (465/522) were pvl positive. Patients with pvl-positive MRSA were more likely than those with pvl-negative MRSA to be young, to be North American, and to present with major abscesses (P < 0.001 for each). Patients were significantly more likely to be cured if they were infected with pvl-positive MRSA than if they were infected with pvl-negative MRSA (91.6% versus 80.7%; P = 0.015). This observation remained statistically significant after adjustment for presence of abscess, fever, or leukocytosis; infection size; diabetes; patient age; and study medication received. The fnbA, cna, sdrC, map-eap, sed, seg, sei, sej, SCCmec type IV, and agr group II genes were also associated with clinical response (P < 0.05). This contemporary, international study demonstrates that pvl was not the primary determinant of outcome in patients with MRSA cSSSI.


Using an integral projection model to assess the effect of temperature on the growth of gilthead seabream Sparus aurata.
Accurate information on the growth rates of fish is crucial for fisheries stock assessment and management. Empirical life history parameters (von Bertalanffy growth) are widely fitted to cross-sectional size-at-age data sampled from fish populations. This method often assumes that environmental factors affecting growth remain constant over time. The current study utilized longitudinal life history information contained in otoliths from 412 juveniles and adults of gilthead seabream, Sparus aurata, a commercially important species fished and farmed throughout the Mediterranean. Historical annual growth rates over 11 consecutive years (2002-2012) in the Gulf of Lions (NW Mediterranean) were reconstructed to investigate the effect of temperature variations on the annual growth of this fish. S. aurata growth was modelled linearly as the relationship between otolith size at year t against otolith size at the previous year t-1. The effect of temperature on growth was modelled with linear mixed effects models and a simplified linear model to be implemented in a cohort Integral Projection Model (cIPM). The cIPM was used to project S. aurata growth, year to year, under different temperature scenarios. Our results determined current increasing summer temperatures to have a negative effect on S. aurata annual growth in the Gulf of Lions. They suggest that global warming already has and will further have a significant impact on S. aurata size-at-age, with important implications for age-structured stock assessments and reference points used in fisheries.


Cerebral hemodynamic changes and pain perception during venipuncture: is glucose really effective?
Newborns are exposed to a considerable number of painful stimuli. This study is aimed to investigate the effects of 30% glucose solution and nonnutritive sucking on pain perception during venipuncture. Twenty-five term infants were randomized as receiving 30% dextrose (group 1) or sterile water (group 2). Neonatal Infant Pain Scale scores, skin conductance algesimeter recordings, and near-infrared spectroscopy measurements were recorded during the procedure. Neonatal Infant Pain Scale and skin conductance algesimeter results were decreased in both groups from that during venipuncture to after the procedure. Group 1 had lower Neonatal Infant Pain Scale scores compared with group 2 after venipuncture, different from the skin conductance algesimeter, where no difference was observed between groups. In group 1, cerebral blood volume increased after venipuncture. Glucose does not attenuate the Neonatal Infant Pain Scale score and skin conductance algesimeter index during venipuncture, but it leads to a lower Neonatal Infant Pain Scale score after venipuncture unlike the skin conductance algesimeter index, which was not lowered.


Alteration of Leukocyte Count Correlates With Increased Pulmonary Vascular Permeability and Decreased PaO2:FiO2 Ratio Early After Major Burns.
Leukocytes are activated systemically and their numbers increase soon after a burn followed by a rapid decline to low normal or subnormal levels, possibly by increased extravasation. Experimental data support that an important target for such extravasation is the lungs and that leukocytes when they adhere to endothelial cells cause an increase in vascular permeability. The authors investigated a possible relation between early increased pulmonary vascular permeability or a decreased PaO2:FiO2 ratio and the dynamic change in concentration of blood leukocytes after a burn. This is a prospective, exploratory, single-center study. The authors measured the dynamic changes of leukocytes in blood starting early after the burn, pulmonary vascular permeability index by thermodilution, and PaO2:FiO2-ratios in 20 patients during the first 21 days after a major burn (>20% TBSA%). Median TBSA was 40% interquartile range (IQR, 25-52) and full thickness burn 28% (IQR, 2-39). There was a correlation between the early (<24 hours) alteration in white blood cell count and both early increased pulmonary vascular permeability (r = .63, P = .004) and the decreased oxygenation index defined as PaO2:FiO2 < 27 kPa (P = .004). The authors have documented a correlation between dynamic change of blood leukocytes and pulmonary failure early after burns.


Increased cardiac performance in mild essential hypertension. Left ventricular mechanics.
To analyze cardiovascular dynamics in essential hypertension, 81 subjects with untreated mild essential hypertension (mean blood pressure, 112 +/- 14 mm Hg) and 87 normotensive subjects from the same working population were studied by echocardiography and simultaneous blood pressure determination. Hypertensive subjects had significantly higher pulse pressure, stroke volume index, cardiac index, left ventricular internal dimension, end-systolic pressure/volume ratio, end-systolic stress, left ventricular mass index, and relative wall thickness than normotensive subjects. Among both normotensive and hypertensive subjects, cardiac performance was closely dependent on afterload, as indicated by close inverse linear relationships between left ventricular fractional shortening and log end-systolic stress (r = -0.83 and -0.78 respectively; both, p less than 0.001). However, 19 of 81 hypertensive patients (23%) fell above the 95% confidence limits of this relationship in normotensive subjects (p less than 0.001 compared with that in normotensive subjects), with a bimodal distribution of fractional shortening as a percent of predicted in relation to end-systolic stress among patients with essential hypertension. This subgroup of hypertensive subjects, with increased resting cardiac performance independent of afterload, was similar in age to the remaining hypertensive subjects but had higher fractional shortening (41 +/- 5% vs 35 +/- 7%; p less than 0.001) and cardiac index (4.3 +/- 1.3 L/min/m2 vs 3.4 +/- 1.0 L/min/m2; p less than 0.005) and lower total peripheral resistance (1257 +/- 502 dyn sec cm-5 vs 1582 +/- 584 dyn sec cm-5 p less than 0.05) and left ventricular relative wall thickness (0.34 +/- 0.06 vs 0.42 +/- 0.10; p less than 0.005). Thus, analysis of cardiac mechanics detected a subset of patients with essential hypertension in whom increased cardiac function cannot be attributed either to relative youth or to supercompensatory left ventricular hypertrophy.


Parthenogenetic activation of rhesus monkey oocytes and reconstructed embryos.
This study determines the efficiency of sequential calcium treatments (electroporation or ionomycin) combined with protein synthesis (cycloheximide) or phosphorylation inhibitors (6-dimethylaminopurine) or the specific maturation promoting factor (MPF) inhibitor, roscovitine, in inducing artificial activation and development of rhesus macaque parthenotes or nuclear transfer embryos. Exposure of oocytes arrested at metaphase II (MII) to ionomycin followed by 6-dimethylaminopurine or to electroporation followed by cycloheximide and cytochalasin B induced pronuclear formation and development to the blastocyst stage at a rate similar to control embryos produced by intracytoplasmic sperm injection. Parthenotes did not complete meiosis or extrude a second polar body, consistent with their presumed diploid status. In contrast, oocytes treated sequentially with ionomycin and roscovitine extruded the second polar body and formed a pronucleus at a rate higher than that observed in controls. Following reconstruction by nuclear transfer, activation with ionomycin/6-dimethylaminopurine resulted in embryos that contained a single pronucleus and no polar bodies. All nuclear transfer embryos activated with ionomycin/roscovitine contained one large pronucleus. However, a third of these embryos emitted one or two polar bodies, clearly containing chromatin material. In summary, we have identified simple yet effective methods of oocyte or cytoplast activation in the monkey, ionomycin/6-dimethylaminopurine, electroporation/cycloheximide/cytochalasin B, and ionomycin/roscovitine, which are applicable to parthenote or nuclear transfer embryo production.


A new, nearly complete stem turtle from the Jurassic of South America with implications for turtle evolution.
Turtles have been known since the Upper Triassic (210Myr old); however, fossils recording the first steps of turtle evolution are scarce and often fragmentary. As a consequence, one of the main questions is whether living turtles (Testudines) originated during the Late Triassic (210Myr old) or during the Middle to Late Jurassic (ca 160Myr old). The discovery of the new fossil turtle, Condorchelys antiqua gen. et sp. nov. from the Middle to Upper Jurassic (ca 160-146Myr old) of South America (Patagonia, Argentina), presented here sheds new light on early turtle evolution. An updated cladistic analysis of turtles shows that C. antiqua and other fossil turtles are not crown turtles, but stem turtles. This cladistic analysis also shows that stem turtles were more diverse than previously thought, and that until the Middle to Upper Jurassic there were turtles without the modern jaw closure mechanism.


State-Level Progress in Reducing the Black-White Infant Mortality Gap, United States, 1999-2013.
To assess state-level progress on eliminating racial disparities in infant mortality. Using linked infant birth-death files from 1999 to 2013, we calculated state-level 3-year rolling average infant mortality rates (IMRs) and Black-White IMR ratios. We also calculated percentage improvement and a projected year for achieving equality if current trend lines are sustained. We found substantial state-level variation in Black IMRs (range = 6.6-13.8) and Black-White rate ratios (1.5-2.7), and also in percentage relative improvement in IMR (range = 2.7% to 36.5% improvement) and in Black-White rate ratios (from 11.7% relative worsening to 24.0% improvement). Thirteen states achieved statistically significant reductions in Black-White IMR disparities. Eliminating the Black-White IMR gap would have saved 64 876 babies during these 15 years. Eighteen states would achieve IMR racial equality by the year 2050 if current trends are sustained. States are achieving varying levels of progress in reducing Black infant mortality and Black-White IMR disparities. Public Health Implications. Racial equality in infant survival is achievable, but will require shifting our focus to determinants of progress and strategies for success.


Photosensitive Accessibility for Interactive Data Visualizations.
Accessibility guidelines place restrictions on the use of animations and interactivity on webpages to lessen the likelihood of webpages inadvertently producing sequences with flashes, patterns, or color changes that may trigger seizures for individuals with photosensitive epilepsy. Online data visualizations often incorporate elements of animation and interactivity to create a narrative, engage users, or encourage exploration. These design guidelines have been empirically validated by perceptual studies in visualization literature, but the impact of animation and interaction in visualizations on users with photosensitivity, who may experience seizures in response to certain visual stimuli, has not been considered. We systematically gathered and tested 1,132 interactive and animated visualizations for seizure-inducing risk using established methods and found that currently available methods for determining photosensitive risk are not reliable when evaluating interactive visualizations, as risk scores varied significantly based on the individual interacting with the visualization. To address this issue, we introduce a theoretical model defining the degree of control visualization designers have over three determinants of photosensitive risk in potentially seizure-inducing sequences: the size, frequency, and color of flashing content. Using an analysis of 375 visualizations hosted on bl.ocks.org, we created a theoretical model of photosensitive risk in visualizations by arranging the photosensitive risk determinants according to the degree of control visualization authors have over whether content exceeds photosensitive accessibility thresholds. We then use this model to propose a new method of testing for photosensitive risk that focuses on elements of visualizations that are subject to greater authorial control - and are therefore more robust to variations in the individual user - producing more reliable risk assessments than existing methods when applied to interactive visualizations. A full copy of this paper and all study materials are available at https://osf.io/8kzmg/.


Deep Brain Stimulation of the Pedunculopontine Nucleus Area in Parkinson Disease: MRI-Based Anatomoclinical Correlations and Optimal Target.
Experimental studies led to testing of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) as a new therapy to treat freezing of gait (FOG) in Parkinson disease (PD). Despite promising initial results fueling a growing interest toward that approach, several clinical studies reported heterogeneity in patient responses. Variation in the position of electrode contacts within the rostral brainstem likely contributes to such heterogeneity. To provide anatomoclinical correlations of the effect of DBS of the caudal mesencephalic reticular formation (cMRF) including the PPN to treat FOG by comparing the normalized positions of the active contacts among a series of 11 patients at 1- and 2-yr follow-up and to provide an optimal target through an open-label study. We defined a brainstem normalized coordinate system in relation to the pontomesencephalic junction. Clinical evaluations were based on a composite score using objective motor measurements and questionnaires allowing classification of patients as "bad responders" (2 patients), "mild responders" (1 patient) and "good responders" (6 patients). Two patients, whose long-term evaluation could not be completed, were excluded from the analysis. Most effective DBS electrode contacts to treat FOG in PD patients were located in the posterior part of the cMRF (encompassing the posterior PPN and cuneiform nucleus) at the level of the pontomesencephalic junction. In the present exploratory study, we performed an anatomoclinical analysis using a new coordinate system adapted to the brainstem in 9 patients who underwent PPN area DBS. We propose an optimal DBS target that allows a safe and efficient electrode implantation in the cMRF.


Role of HD2 genes in seed germination and early seedling growth in Arabidopsis.
The Arabidopsis HD2 family of histone deacetylases consist of 4 members (HD2A, HD2B, HD2C, HD2D) that play diverse roles in plant development and physiology through chromatin remodelling. Here, we show that the transcripts of HD2 family members selectively accumulate in response to glucose through a HXK1-independent signal transduction pathway during the early stages of seedling growth. Germination was enhanced in hd2a null mutants relative to wild-type seeds. In contrast, hd2c mutants were restrained in germination relative to wild-type seeds. In hd2a/hd2c double mutants, germination was restored to wild-type levels. The data suggests that HD2A and HD2C may have different and opposing functions in germination with the glucose/HD2A pathway acting to restrain germination and the HD2C pathway acting to enhance germination. These pathways may function early in the regulation of seedling germination, independently of the glucose/HXK1/ABA signal transduction pathway, to fine tune the onset of germination.


A comparative randomized study on the efficacy of a systemic steroid therapy vs. a thermal therapy in otitis media with effusion in children.
The aim of this study was to compare the effectiveness of a systemic steroid therapy vs. a thermal therapy based on sulphurous water insufflation. The therapy was performed in Telese Terme Spa based on the Salimbani-Politzer technique on children suffering of otitis media with effusion (OME), using the variations of the tympanogram as objective outcome in a short time follow-up. Eighty children suffering of monolateral or bilateral OME (44 male, 36 female, age 4-12 years, average age 7.2±2.83 ys.), enrolled in ENT or paediatrics offices, have been included in the study. Children were included in a randomization list in order to obtain two therapeutic groups, the first one to be treated through a systemic steroid therapy, the second one to be treated through sulphuruos water insufflation in Telese Spa. Children underwent otoscopic/otomicroscopic visit and tympanometry before the beginning of the therapy (T0), 7 days after the beginning of the therapy (T1), 7-10 days after the end of the therapy (T2), 30-35 days after the end of the therapy (T3). The variation of the type of tympanogram was considered the objective outcome. The shift either from a type B to a type C or o type A tympanogram and from a type C to a type A tympanogram was considered a positive outcome; the persistence either of the same type of tympanogram and the shift from a type C to a type B or from a type A to a type C or a type B were considered a negative outcome. Thermal therapy showed better outcomes at each time, with differences in improvement and healing often reaching the statistical significance. The most important prognostic indicator was the presence of an initial type B tympanogram, associated to a worst prognosis in both therapeutic groups and in each subgroup of OME. Sulphurous water insufflation therapy appeared a good therapeutic choose in the treatment of OME in a pediatric population.


Dietary patterns, Mediterranean diet, and cardiovascular disease.
The objective of this manuscript was to review the evidence on the association between adherence to a Mediterranean diet (MeDiet) and the risk of cardiovascular disease (CVD). We also updated the results of the last available meta-analysis. In 2013, a landmark study in the field, the PREvención con DIeta MEDiterránea randomized trial, with 7447 high-risk participants, published its final results. They provided a strong support to the beneficial role of a traditional MeDiet for primary cardiovascular prevention. When these results were combined with those of the Lyon Diet Heart Study (a secondary prevention trial), we found that an intervention with a MeDiet was associated with a 38% relative reduction in the risk of CVD clinical events (pooled random-effects risk ratio: 0.62; 95% confidence interval, CI: 0.45-0.85). Regarding observational studies assessing clinical end-points as outcome, we identified seven new cohort studies published after the last meta-analysis. After removing studies that only assessed fatal outcomes, a two-point increase in adherence to the MeDiet (0-9 score) was associated with a significant reduction in cardiovascular events (pooled risk ratio: 0.87; 95% CI: 0.85-0.90) with no evidence of heterogeneity. Consistent evidence suggests that the promotion of the Mediterranean dietary pattern is an effective and feasible tool for the prevention of CVD.


Ce-doped YAG nanophosphor and red emitting CuInS2/ZnS core/shell quantum dots for warm white light-emitting diode with high color rendering index.
In this work, we report the solvothermal synthesis of Ce-doped YAG (YAG:Ce) nanoparticles (NPs) and their association with a free-Cd CuInS2/ZnS (CIS/ZnS) core/shell QDs for application into white light emitting diode (WLED). 1500 °C-annealed YAG:Ce NPs and CIS/ZnS core/shell QDs exhibited intense yellow and red emissions band with maxima at 545 and 667 nm, respectively. Both YAG:Ce nanophosphor and CIS/ZnS QDs showed high photoluminescence quantum yield (PL QY) of about 50% upon 460 nm excitation. YAG:Ce nanophosphor layer and bilayered YAG:Ce nanophosphor-CIS/ZnS QDs were applied on blue InGaN chip as converter wavelength to achieve WLED. While YAG:Ce nanophosphor converter layer showed low color rendering index (CRI) and cold white light, bilayered YAG:Ce nanophosphor-CIS/ZnS QDs displayed higher CRI of about 84 and warm white light with a correlated color temperature (CCT) of 2784 K. WLED characteristics were measured as a function of forward current from 20 to 1200 mA. The white light stability of bilayered nanophosphor-QDs-based WLED operated at 200 mA was also studied as a function of operating time up to 40 h. Interestingly, CRI and CCT of such device tend to remain constant after 7 h of operating time suggesting that layer-by-layer structure of YAG:Ce phosphor and red-emitting CIS/ZnS QDs could be a good solution to achieve stable warm WLED, especially when high current density is applied.


Native American embodiment of the chronicities of modernity: reservation food, diabetes, and the metabolic syndrome among the Kiowa, Comanche, and Apache.
As a physical embodiment of modernity, the prevalence of obesity, diabetes, and the metabolic syndrome (MetS) among Native Americans reflects their body's biological response to social and cultural structures that routinize daily behaviors and contain their physical body. This article explains why Native Americans were one of the earliest populations manifesting this epidemic. Ethnohistorical methods identify the conjuncture of chronic behaviors among Kiowa, Comanche, and Apache of Oklahoma that promote inactivity, overnutrition, and psychosocial stresses. Correspondence and primary documents of Federal Indian Agents who managed the reservation food rations and annuity systems beginning in the 1860s, details a culture history of nutrition and food technologies that standardized and established the unhealthy modern diet that continues among Native Americans today. By identifying structural chronicities affecting specific populations and life situations, policies and interventions can be more effective in promoting positive changes for reducing the global pandemic of diabetes and MetS.


Data integration and visualization system for enabling conceptual biology.
Integration of heterogeneous data in life sciences is a growing and recognized challenge. The problem is not only to enable the study of such data within the context of a biological question but also more fundamentally, how to represent the available knowledge and make it accessible for mining. Our integration approach is based on the premise that relationships between biological entities can be represented as a complex network. The context dependency is achieved by a judicious use of distance measures on these networks. The biological entities and the distances between them are mapped for the purpose of visualization into the lower dimensional space using the Sammon's mapping. The system implementation is based on a multi-tier architecture using a native XML database and a software tool for querying and visualizing complex biological networks. The functionality of our system is demonstrated with two examples: (1) A multiple pathway retrieval, in which, given a pathway name, the system finds all the relationships related to the query by checking available metabolic pathway, transcriptional, signaling, protein-protein interaction and ontology annotation resources and (2) A protein neighborhood search, in which given a protein name, the system finds all its connected entities within a specified depth. These two examples show that our system is able to conceptually traverse different databases to produce testable hypotheses and lead towards answers to complex biological questions.


Eupatilin Inhibits Gastric Cancer Cell Growth by Blocking STAT3-Mediated VEGF Expression.
Eupatilin is an antioxidative flavone and a phytopharmaceutical derived from Artemisia asiatica. It has been reported to possess anti-tumor activity in some types of cancer including gastric cancer. Eupatilin may modulate the angiogenesis pathway which is part of anti-inflammatory effect demonstrated in gastric mucosal injury models. Here we investigated the anti-tumor effects of eupatilin on gastric cancer cells and elucidated the potential underlying mechanism whereby eupatilin suppresses angiogenesis and tumor growth. The impact of eupatilin on the expression of angiogenesis pathway proteins was assessed using western blots in MKN45 cells. Using a chromatin immunoprecipitation assay, we tested whether eupatilin affects the recruitment of signal transducer and activator of transcription 3 (STAT3), aryl hydrocarbon receptor nuclear translocator (ARNT) and hypoxia-inducible factor-1α (HIF-1α) to the human VEGF promoter. To investigate the effect of eupatilin on vasculogenesis, tube formation assays were conducted using human umbilical vein endothelial cells (HUVECs). The effect of eupatilin on tumor suppression in mouse xenografts was assessed. Eupatilin significantly reduced VEGF, ARNT and STAT3 expression prominently under hypoxic conditions. The recruitment of STAT3, ARNT and HIF-1α to the VEGF promoter was inhibited by eupatilin treatment. HUVECs produced much foreshortened and severely broken tubes with eupatilin treatment. In addition, eupatilin effectively reduced tumor growth in a mouse xenograft model. Our results indicate that eupatilin inhibits angiogenesis in gastric cancer cells by blocking STAT3 and VEGF expression, suggesting its therapeutic potential in the treatment of gastric cancer.


Zinc deprivation promotes progression of 1,2-dimethylhydrazine-induced colon tumors but reduces malignant invasion in mice.
The aim of this study was to characterize colon tumor development and invasiveness associated with dietary zinc deprivation. Colon carcinogenesis was initiated by eight weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH) at 12 mg DMH base/kg body wt in groups of mice maintained on diets containing 30 micrograms/kg dietary zinc (zinc adequate, ZA) or 3 micrograms/kg dietary zinc (zinc deprived, ZD). All mice were killed 24 weeks after the last injection of DMH. Mean zinc concentration in the liver was significantly lower in the ZD group than in the ZA group. The total number of grossly detectable colon tumors was the same in both dietary groups. However, histopathological study of each tumor revealed significantly more adenomatous polyps (AP) and invasive adenocarcinomas (CA) in the ZA group, whereas the ZD group had significantly more noninvasive carcinomas in situ (CIS). It appears that zinc deprivation stimulated progression of AP to noninvasive CIS but retarded the progression of noninvasive CIS to invasive CA. Immunohistochemistry of tumors from ZA and ZD mice indicated increased amounts of type IV collagenase in epithelial tumor cells and in stromal cells adjacent to tumor tissue regardless of the amount of dietary zinc consumed. It is suggested that zinc deprivation may limit function of zinc-requiring enzymes such as superoxide dismutase and type IV collagenase, resulting in enhanced progression of AP to noninvasive CIS and retardation of invasion of CIS to become CA, respectively.


Alarming spread of vancomycin resistant enterococci in Sweden since 2007.
The total number of persons infected or colonised with vancomycin-resistant enterococci mandatorily reported to the Swedish Institute for Infectious Disease Control increased dramatically during 2007 and 2008. During a period of twenty months from 1 July 2007 to 28 February 2009, a total of 760 cases were reported compared with 194 cases reported during the entire period from 2000 to 2006. This rise was mainly attributed to a wide dissemination of vancomycin resistant enterococci which started in a number of hospitals in Stockholm in the autumn of 2007 and was followed by dissemination in various healthcare facilities (hospitals and homes for the elderly) in a further two Swedish counties in 2008. The majority of the cases (97%) were acquired in Sweden and among these, healthcare-acquired E. faecium vanB dominated (n=634). The majority of these isolates had identical or closely related pulsed-field gel electrophoresis patterns indicating clonal dissemination in the affected counties. The median minimum inhibitory concentration of vancomycin was 32 mg/L (ranging from 4 to >128 mg/L) and of teichoplanin 0.12 mg/L (ranging from 0.06 to 0.25 mg/L). Particular emphasis was placed on countermeasures such as screening, contact tracing, cleaning procedures, education in accurate use of infection control practices as well as increasing awareness of hygiene among patients and visitors. With these measures the dissemination rate decreased substantially, but new infections with the E. faecium vanB strain were still detected.


PETROTOX: an aquatic toxicity model for petroleum substances.
A spreadsheet model (PETROTOX) is described that predicts the aquatic toxicity of complex petroleum substances from petroleum substance composition. Substance composition is characterized by specifying mass fractions in constituent hydrocarbon blocks (HBs) based on available analytical information. The HBs are defined by their mass fractions within a defined carbon number range or boiling point interval. Physicochemical properties of the HBs are approximated by assigning representative hydrocarbons from a database of individual hydrocarbons with associated physicochemical properties. A three-phase fate model is used to simulate the distribution of each structure among the water-, air-, and oil-phase liquid in the laboratory test system. Toxicity is then computed based on the predicted aqueous concentrations and aquatic toxicity of each structure and the target lipid model. The toxicity of the complex substance is computed assuming additivity of the contribution of the individual assigned hydrocarbons. Model performance was evaluated by using direct comparisons with measured toxicity data for petroleum substances with sufficient analytical characterization to run the model. Indirect evaluations were made by comparing predicted toxicity distributions using analytical data on petroleum substances from different product categories with independent, empirical distributions of toxicity data available for the same categories. Predictions compared favorably with measured aquatic toxicity data across different petroleum substance categories. These findings demonstrate the utility of PETROTOX for assessing environmental hazards of petroleum substances given knowledge of substance composition.


Point of Care eGFR and the Prediction of Outcomes in Pneumonia.
Pneumonia is a leading cause of mortality. Severity-assessment scores in pneumonia guide treatment crucially, but the ones currently in existence are limited in their use. Community-based studies demonstrated the association between pre-existing low estimated glomerular filtration rate (eGFR) and outcomes in pneumonia. However, whether a single emergency department-eGFR measurement could predict outcomes in pneumonia remains unclear. This retrospective cohort study included 1554 patients hospitalized with pneumonia. The predictor was the first eGFR measurement. Outcomes included mortality, intensive care unit (ICU) admission, durations of hospital and ICU stay, and ventilator use. Receiver operating characteristic curves was used to determine optimal cutoff values to predict mortality. Of 1554 patients, 263 had chronic kidney disease, demonstrated higher C-reactive protein and SMART-COP scores, and had more multilobar pneumonia, acute kidney injury, ICU admission, and mortality. Patients with higher pneumonia severity scores tended to have lower eGFR. For predicting in-hospital mortality, the optimal eGFR cutoff value was 56 mL/min/1.73 m2. eGFR < 56 mL/min/1.73 m2 had an odds ratio of 2.5 (95% confidence interval, 1.6-4.0) for mortality by multivariate logistic regression. In Conclusion, eGFR < 56 mL/min/1.73 m2 is an independent predictor of mortality, indicating that even mild renal impairment affects the outcome of pneumonia adversely.


Antibiotic resistance of Streptococcus pneumoniae colonising the nasopharynx of HIV-exposed Tanzanian infants.
To determine antibiotic susceptibility of colonising pneumococcal serotypes in HIV-exposed infants before the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13), because HIV-exposed infants are at increased risk of invasive pneumococcal infections. Antibiotic susceptibility of 104 pneumococcal isolates, cultured from the nasopharynx from Tanzanian HIV-exposed infants, was determined using the disc diffusion method and the E-test according to EUCAST version 4.0 (2014) criteria. A total of 69.2% of isolates were intermediately susceptible for benzyl penicillin (MIC 0.06-2 mg/l ); no high-level resistance was found. All isolates but one were susceptible to ampicillin. Regarding non-beta-lactam antibiotics, 19.2% of isolates were resistant to doxycycline, 3.8% to erythromycin and 97.1% to trimethoprim/sulfamethoxazole. A total of 15.4% of isolates were resistant to three antibiotic classes or more. There were no differences in antibiotic susceptibility between vaccine and non-vaccine serotypes. Reduced susceptibility of colonising pneumococcal isolates for commonly used antibiotics is common in HIV-exposed Tanzanian infants. High-dose penicillin and ampicillin remain appropriate first choices for non-meningeal pneumococcal infections in this group.


Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma.
Rhabdomyosarcoma (RMS) of the biliary tract is rare, and, in addition to multiagent chemotherapy with or without radiotherapy (RT), some investigators recommend aggressive surgery. To assess the role of surgery, records of all 25 eligible patients with biliary RMS enrolled in IRSG studies I through IV from 1972 to 1998 were reviewed. Treatment included surgery with or without vincristine, dactinomycin, cyclophosphamide, doxorubicin, cisplatin, etoposide, ifosfamide, and with or without RT. Data evaluated included clinical presentation, treatment, complications, and outcome. Diagnostic imaging identified the primary tumor but failed to identify regional metastases. Despite aggressive surgery, gross total resection at diagnosis was possible in only 6 cases, 2 of which had negative surgical margins. Although only 6 (29%) patients without distant metastases underwent gross total resection, estimated 5-year survival rate was 78% (95% CI 58%, 97%). Infectious complications were common and frequently associated with external biliary drains. Five (20%) died within the first 2 months, 3 of sepsis. Surgery is critical for establishing an accurate diagnosis and determining the extent of regional disease. Gross total resection is rarely possible despite aggressive surgery, and outcome is good despite residual disease after surgery. External biliary drains increase the risk of postoperative infectious complications.


Community Attitudes Toward Mass Drug Administration for Control and Elimination of Neglected Tropical Diseases After the 2014 Outbreak of Ebola Virus Disease in Lofa County, Liberia.
The recent outbreak of Ebola virus disease (EVD) interrupted mass drug administration (MDA) programs to control and eliminate neglected tropical diseases in Liberia. MDA programs treat entire communities with medication regardless of infection status to interrupt transmission and eliminate lymphatic filariasis and onchocerciasis. Following reports of hostilities toward health workers and fear that they might be spreading EVD, it was important to determine whether attitudes toward MDA might have changed after the outbreak. We surveyed 140 community leaders from 32 villages in Lofa County, Liberia, that had previously participated in MDA and are located in an area that was an early epicenter of the EVD outbreak. Survey respondents reported a high degree of community trust in the MDA program, and 97% thought their communities were ready to resume MDA. However, respondents predicted that fewer people would comply with MDA after the EVD epidemic than before. The survey also uncovered fears in the community that EVD and MDA might be linked. Respondents suggested that MDA programs emphasize to people that the medications are identical to those previously distributed and that MDA programs have nothing to do with EVD.


A survey of the humoral immune response of cancer patients to a panel of human tumor antigens.
Evidence is growing for both humoral and cellular immune recognition of human tumor antigens. Antibodies with specificity for antigens initially recognized by cytotoxic T lymphocytes (CTLs), e.g., MAGE and tyrosinase, have been detected in melanoma patient sera, and CTLs with specificity for NY-ESO-1, a cancer-testis (CT) antigen initially identified by autologous antibody, have recently been identified. To establish a screening system for the humoral response to autoimmunogenic tumor antigens, an enzyme-linked immunosorbent assay (ELISA) was developed using recombinant NY-ESO-1, MAGE-1, MAGE-3, SSX2, Melan-A, and tyrosinase proteins. A survey of sera from 234 cancer patients showed antibodies to NY-ESO-1 in 19 patients, to MAGE-1 in 3, to MAGE-3 in 2, and to SSX2 in 1 patient. No reactivity to these antigens was found in sera from 70 normal individuals. The frequency of NY-ESO-1 antibody was 9.4% in melanoma patients and 12.5% in ovarian cancer patients. Comparison of tumor NY-ESO-1 phenotype and NY-ESO-1 antibody response in 62 stage IV melanoma patients showed that all patients with NY-ESO-1(+) antibody had NY-ESO-1(+) tumors, and no patients with NY-ESO-1(-) tumors had NY-ESO-1 antibody. As the proportion of melanomas expressing NY-ESO-1 is 20-40% and only patients with NY-ESO-1(+) tumors have antibody, this would suggest that a high percentage of patients with NY-ESO-1(+) tumors develop an antibody response to NY-ESO-1.


Serological response to Helicobacter pylori recombinant antigens in Chilean infected patients with duodenal ulcer, non-ulcer dyspepsia and gastric cancer.
We have previously cloned 10 Helicobacter pylori antigen genes from a Chilean strain including: cytotoxin VacA, a truncated region of CagA (called A17), a species-specific protein (Ag26), urease subunits (UreA, UreB), a flagellin, (FlaB), heat shock proteins (HspA and HspB), an adhesin (HpaA) and a lipoprotein (Lpp20). Immunogenicity of these antigens was tested by immunoblot with sera of Chilean infected patients, revealing that HpaA, A17, HspB and VacA were more frequently recognized (86%, 82%, 68% and 68%, respectively). According to the clinical condition, it was determined that Lpp20 was preferentially recognized by sera from non-ulcer dyspepsia patients (80%), A17 and VacA by patients with duodenal ulcer (92% and 83% respectively), and HspB by patients with duodenal ulcer (83%) and gastric cancer (90%). An ELISA was developed with a purified mixture of A17 and VacA antigens to test the different groups of patients. It was found that sera from duodenal ulcer patients showed higher values than those from non-ulcer dyspepsia patients, but this difference was not significant (p<0.2). Moreover, sera from gastric cancer patients showed values lower than those from non-ulcer dyspepsia patients (p<0.019). These results indicate that, in the Chilean population, antibodies raised against VacA and A 7 are not markers either for duodenal ulcer or for gastric cancer.


Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD.
To conduct a post hoc pharmacoeconomic evaluation of two double-blind, randomized, prospective, parallel group studies comparing the long-term efficacy and safety of ipratropium combined with albuterol in a single inhalational canister against either bronchodilator agent alone in patients with COPD. One thousand sixty-seven patients with COPD. The dose of each bronchodilator was two puffs four times a day (42 microg of ipratropium bromide, 240 microg of albuterol sulfate). Pulmonary function testing was performed on days 1, 29, 57, and 85 of treatment. Outcomes, health-care resource consumption, and costs were compared for the three treatment groups over the 85-day study period. A total of 1,067 patients were randomized in the two studies (albuterol alone, n = 347; ipratropium alone, n = 362; albuterol plus ipratropium, n = 358). Improvement in FEV1 and area under the FEV1 response-time curve from time 0 to 4 h (FEV1AUC0-4) was significantly greater for the combination of albuterol plus ipratropium than either agent alone on all test days. Compared with albuterol, patients receiving ipratropium and ipratropium plus albuterol experienced significantly fewer COPD exacerbations and patient-days of exacerbation. In addition, the increased frequency of exacerbations observed in the albuterol group was associated with a significant increase in the number of patient hospital days and antibiotic and corticosteroid use. As a result, the total cost of treatment over the study period was significantly less for ipratropium ($156 per patient) and ipratropium plus albuterol ($197 per patient) than for albuterol ($269 per patient). Increased cost-effectiveness, defined as total estimated treatment cost per mean change in FEV1AUC0-4, was observed in both treatment arms containing ipratropium. The inclusion of ipratropium in a pharmacologic treatment regimen is associated with a lower rate of exacerbations in COPD. The result is lower total treatment costs and improved cost-effectiveness.


Utility of primary cells to examine NPC1 receptor expression in Mops condylurus, a potential Ebola virus reservoir.
The significance of the integral membrane protein Niemann-Pick C1 (NPC1) in the ebolavirus entry process has been determined using various cell lines derived from humans, non-human primates and fruit bats. Fruit bats have long been purported as the potential reservoir host for ebolaviruses, however several studies provide evidence that Mops condylurus, an insectivorous microbat, is also an ebolavirus reservoir. NPC1 receptor expression in the context of ebolavirus replication in microbat cells remains unstudied. In order to study Ebola virus (EBOV) cellular entry and replication in M. condylurus, we derived primary and immortalized cell cultures from 12 different organs. The NPC1 receptor expression was characterized by confocal microscopy and flow cytometry comparing the expression levels of M. condylurus primary and immortalized cells, HeLa cells, human embryonic kidney cells and cells from a European microbat species. EBOV replication kinetics was studied for four representative cell cultures using qRT-PCR. The aim was to elucidate the suitability of primary and immortalized cells from different tissues for studying NPC1 receptor expression levels and their potential influence on EBOV replication. The NPC1 receptor expression level in M. condylurus primary cells differed depending on the organ they were derived from and was for most cell types significantly lower than in human cell lines. Immortalized cells showed for most cell types higher expression levels than their corresponding primary cells. Concluding from our infection experiments with EBOV we suggest a potential correlation between NPC1 receptor expression level and virus replication rate in vitro.


Quality of information sources about mental disorders: a comparison of Wikipedia with centrally controlled web and printed sources.
Although mental health information on the internet is often of poor quality, relatively little is known about the quality of websites, such as Wikipedia, that involve participatory information sharing. The aim of this paper was to explore the quality of user-contributed mental health-related information on Wikipedia and compare this with centrally controlled information sources. Content on 10 mental health-related topics was extracted from 14 frequently accessed websites (including Wikipedia) providing information about depression and schizophrenia, Encyclopaedia Britannica, and a psychiatry textbook. The content was rated by experts according to the following criteria: accuracy, up-to-dateness, breadth of coverage, referencing and readability. Ratings varied significantly between resources according to topic. Across all topics, Wikipedia was the most highly rated in all domains except readability. The quality of information on depression and schizophrenia on Wikipedia is generally as good as, or better than, that provided by centrally controlled websites, Encyclopaedia Britannica and a psychiatry textbook.


Microsomal glutathione transferase 1 exhibits one-third-of-the-sites-reactivity towards glutathione.
The trimeric membrane protein microsomal glutathione transferase 1 (MGST1) possesses glutathione transferase and peroxidase activity. Previous data indicated one active site/trimer whereas structural data suggests three GSH-binding sites. Here we have determined ligand interactions of MGST1 by several techniques. Nanoelectrospray mass spectrometry of native MGST1 revealed binding of three GSH molecules/trimer and equilibrium dialysis showed three product molecules/trimer (K(d)=320+/-50 microM). All three product molecules could be competed out with GSH. Reinvestigation of GSH-binding showed one high affinity site per trimer, consistent with earlier data. Using single turnover stopped flow kinetic measurements, K(d) could be determined for a low affinity GSH-binding site (2.5+/-0.5 mM). Thus we can reconcile previous observations and show here that MGST1 contains three active sites with different affinities for GSH and that only the high affinity site is catalytically competent.


Treatment patterns and steroid dose for adult minimal change disease relapses: A retrospective cohort study.
In patients with adult minimal change disease (MCD), proteinuria relapse is a problem to solve. However, the optimal relapse treatment regimen remains unclear regarding steroid dose. We described the treatment pattern of adult MCD patients and evaluated the appropriate steroid dose for relapse treatment. This retrospective multicenter cohort study included 192 patients with adult biopsy-proven MCD from 14 hospitals in Japan. The prescription pattern of immunosuppressive drugs in relapse was reviewed. To assess the association between steroid dose used for relapse and subsequent outcomes, data of patients with tapered prednisolone (PSL) dosage to <10 mg/day before the first relapse in whom the dose was subsequently increased to ≥10 mg/day were extracted and assigned to the High-PSL or Low-PSL groups, based on the median dose of 20 mg/day. Multivariate Cox proportional hazard model and propensity score analysis with multiple imputations were conducted to compare their clinical course. During a median observation period of 37.6 months, 186/192 (96.9%) patients achieved complete remission (CR) and 100 (52.1%) relapsed. The median urinary protein level at the first relapse was 3.12 g/gCr or g/day. The proportion of non-steroidal immunosuppressant use increased with relapses; cyclosporine was the most common. No significant differences were found in the second relapse, frequent relapses, or adverse events between High-PSL (n = 34) and Low-PSL (n = 36) groups. A multivariate Cox proportional hazard model revealed that the hazard ratios adjusted with propensity score for the second relapse were 0.94 (High-PSL vs. Low-PSL; 95% confidence interval, 0.42-2.10; P = 0.88) and 0.82 (PSL dose per 10 mg/day; 95% confidence interval, 0.58-1.16; P = 0.25). Among patients in CR with PSL dose <10 mg/day, higher steroid dose (PSL >20 mg/day) was not associated with favorable outcomes after the first relapse as compared to lower dose (10-20 mg/day).


The use of single armed observational data to closing the gap in otherwise disconnected evidence networks: a network meta-analysis in multiple myeloma.
Network meta-analysis (NMA) allows for the estimation of comparative effectiveness of treatments that have not been studied in head-to-head trials; however, relative treatment effects for all interventions can only be derived where available evidence forms a connected network. Head-to-head evidence is limited in many disease areas, regularly resulting in disconnected evidence structures where a large number of treatments are available. This is also the case in the evidence of treatments for relapsed or refractory multiple myeloma. Randomised controlled trials (RCTs) identified in a systematic literature review form two disconnected evidence networks. Standard Bayesian NMA models are fitted to obtain estimates of relative effects within each network. Observational evidence was identified to fill the evidence gap. Single armed trials are matched to act as each other's control group based on a distance metric derived from covariate information. Uncertainty resulting from including this evidence is incorporated by analysing the space of possible matches. Twenty five randomised controlled trials form two disconnected evidence networks; 12 single armed observational studies are considered for bridging between the networks. Five matches are selected to bridge between the networks. While significant variation in the ranking is observed, daratumumab in combination with dexamethasone and either lenalidomide or bortezomib, as well as triple therapy of carfilzomib, ixazomib and elozumatab, in combination with lenalidomide and dexamethasone, show the highest effects on progression free survival, on average. The analysis shows how observational data can be used to fill gaps in the existing networks of RCT evidence; allowing for the indirect comparison of a large number of treatments, which could not be compared otherwise. Additional uncertainty is accounted for by scenario analyses reducing the risk of over confidence in interpretation of results.


The long-term prognosis for live birth in couples initiating fertility treatments.
What are the long-term chances of having a child for couples starting fertility treatments and how many conceive with ART, IUI and without treatment? Total 5-year live birthrates were strongly influenced by female age and ranged from 80% in women under 35-26% in women ≥40 years, overall, 14% of couples conceived naturally and one-third of couples starting treatments with intrauterine insemination delivered from that treatment. Few studies report success rates in fertility treatments across a couple's complete fertility treatment history, across clinics, evaluating live births after insemination, ART and natural conceptions. This register-based national cohort study from Denmark includes all women initiating fertility treatments in public and private clinics with homologous gametes in 2007-2010. Women were identified in the Danish ART Registry and were cross-linked with the Medical Birth Registry to identify live births. Subfertile couples were followed 2 years (N = 19 884), 3 years (N = 14 445) and 5 years (N = 5165), or until their first live birth. Cumulative live birthrates were estimated 2, 3 and 5 years from the first treatment cycle, in all women, including drop-outs. Birthrates were stratified by type of first treatment (ART/IUI), mode of conception (ART/IUI/natural conception) and female age. Within 5 years, in women aged <35 years (N = 3553), 35-39 years (N = 1156) and ≥40 years (N = 451), a total of 64%, 49% and 16% had a live birth due to treatment, respectively. Additionally, in women aged < 35 years, 35-39 years and ≥40 years, 16%, 11% and 10% delivered after natural conception, yielding total 5-year birthrates of 80%, 60% and 26%. In women starting treatments with IUI (N = 3028), 35% delivered after IUI within 5 years, 24% delivered after shift to ART treatments and 17% delivered after natural conception. Within 5 years from starting treatments with ART (N = 2137), 53% delivered after ART, 11% delivered after natural conception and 0.6% delivered after IUI. Birthrates are most likely higher compared to countries without national coverage of treatments and results are influenced by laws and regulations. Information on duration of infertility prior to treatment was not available. Future prospective intervention studies should focus on the role of expectant management. Our results can provide couples with a comprehensible age-stratified prognosis at start of treatment. This study was unconditionally funded by Ferring Pharmaceuticals and the Augustinus foundation. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: S.S.M. received an unconditional grant from Ferring Pharmaceuticals; A.A.H. has received personal fees from Ferring Pharmaceuticals not related to this work; A.N.A. reports grants and personal fees from Ferring Pharmaceuticals, personal fees from Merck Serono, grants and personal fees from MSD, outside the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. The study was approved by the Danish Data Protection Agency (J.nr. 2012-41-1330).


Global transcriptome analysis reveals distinct expression among duplicated genes during sorghum-interaction.
Sorghum (Sorghum bicolor L. Moench) is a rich source of natural phytochemicals. We performed massive parallel sequencing of mRNA to identify differentially expressed genes after sorghum BTx623 had been infected with Bipolaris sorghicola, a necrotrophic fungus causing a sorghum disease called target leaf spot. Seventy-six-base-pair reads from mRNAs of mock- or pathogen-infected leaves were sequenced. Unannotated transcripts were predicted on the basis of the piling-up of mapped short reads. Differentially expressed genes were identified statistically; particular genes in tandemly duplicated putative paralogs were highly upregulated. Pathogen infection activated the glyoxylate shunt in the TCA cycle; this changes the role of the TCA cycle from energy production to synthesis of cell components. The secondary metabolic pathways of phytoalexin synthesis and of sulfur-dependent detoxification were activated by upregulation of the genes encoding amino acid metabolizing enzymes located at the branch point between primary and secondary metabolism. Coordinated gene expression could guide the metabolic pathway for accumulation of the sorghum-specific phytochemicals 3-deoxyanthocyanidin and dhurrin. Key enzymes for synthesizing these sorghum-specific phytochemicals were not found in the corresponding region of the rice genome. Pathogen infection dramatically changed the expression of particular paralogs that putatively encode enzymes involved in the sorghum-specific metabolic network.


Differences in maintenance of response upon discontinuation across medication treatments in attention-deficit/hyperactivity disorder.
The attention-deficit/hyperactivity disorder (ADHD) treatment literature has been focused on onset-of-effect and short-term effect size, with little exploration of ADHD symptoms upon medication discontinuation. The objective of this narrative review and analysis was to better understand the relapse of ADHD symptoms upon discontinuation of medication treatment in children, adolescents, and adults with ADHD who have responded to medication treatment and to explore differences among different medications in maintaining treatment response. Randomized withdrawal studies of dexmethylphenidate hydrochloride (d-MPH), methylphenidate modified-release (MPH-LA), lisdexamphetamine dimesylate (LDX), guanfacine extended-release (GXR), and atomoxetine (ATX) in both children/adolescents and adults with ADHD were reviewed. The percentage of relapse was significantly higher and the time-to-relapse significantly shorter with placebo compared to active treatment in patients who were previously stable on 5 weeks to 1 year of active treatment, suggesting clinically significant benefit with continued long-term pharmacotherapy. However, percentage of relapse at each time point studied after discontinuing stimulants and GXR appears substantially higher than observed when discontinuing ATX, suggesting longer maintenance of response after discontinuing ATX than after stimulants and GXR. Additionally, slope of relapse percentages over time appears to be more rapid with stimulants or GXR than with ATX. These differences in maintenance of response among ATX, GXR, and stimulants may reflect differences in mechanisms of action and persistence of the medication effect. Alternatively, they may be due to methodological differences, including study design and response/relapse definitions. Continued investigation is needed regarding factors that affect risk of symptom relapse upon discontinuation of pharmacotherapy.


Expression of naked DNA in human, pig, and mouse skin.
The insertion and expression of genes in the epidermis may have a variety of therapeutic uses, including the treatment of skin diseases. Here we show that when both human skin organ cultures and human skin grafts on immunocompromised mice are injected with naked DNA, the DNA is taken-up and genes are expressed in the epidermis in a manner similar to both pig skin injected in vivo and injected pig skin organ cultures. In contrast, DNA injected into mouse skin is expressed not just in the epidermis, but also in the dermis and underlying fat and muscle tissue, and is expressed at lower levels. These findings suggest that genes can be expressed in human skin, after injection of naked DNA, and indicate that pig skin is an appropriate model for the study of DNA uptake and gene expression in human skin. The organ cultures of human and pig skin may be useful in understanding how naked DNA is internalized and expressed after in vivo injections. Additionally, skin obtained from patients with skin disease may be studied as skin grafts and organ cultures to help optimize genetic approaches for the treatment of skin diseases prior to clinical trials, by determining if the injected gene can provide a therapeutic benefit.


ERGO: Breaking Down the Wall between Human Health and Environmental Testing of Endocrine Disrupters.
ERGO (EndocRine Guideline Optimization) is the acronym of a European Union-funded research and innovation action, that aims to break down the wall between mammalian and non-mammalian vertebrate regulatory testing of endocrine disruptors (EDs), by identifying, developing and aligning thyroid-related biomarkers and endpoints (B/E) for the linkage of effects between vertebrate classes. To achieve this, an adverse outcome pathway (AOP) network covering various modes of thyroid hormone disruption (THD) in multiple vertebrate classes will be developed. The AOP development will be based on existing and new data from in vitro and in vivo experiments with fish, amphibians and mammals, using a battery of different THDs. This will provide the scientifically plausible and evidence-based foundation for the selection of B/E and assays in lower vertebrates, predictive of human health outcomes. These assays will be prioritized for validation at OECD (Organization for Economic Cooperation and Development) level. ERGO will re-think ED testing strategies from in silico methods to in vivo testing and develop, optimize and validate existing in vivo and early life-stage OECD guidelines, as well as new in vitro protocols for THD. This strategy will reduce requirements for animal testing by preventing duplication of testing in mammals and non-mammalian vertebrates and increase the screening capacity to enable more chemicals to be tested for ED properties.


The Implementation Process for Pharmacogenomic Testing for Cancer-Targeted Therapies.
Recent advances in genomic medicine have led to the availability of genomic tests that have the potential to improve population health, yet the process for obtaining these tests and getting them reimbursed by insurers has not been described. The objective of this study was to describe the process of ordering pharmacogenomic tests by interviewing providers, patients, and laboratories about cancer-related pharmacogenomic tests. We interviewed patients who were prescribed, providers who prescribed medications that should be guided by pharmacogenomic testing, and individuals from diagnostic laboratories. A total of 10 providers, 16 patients, and eight diagnostic laboratories described logistical and insurance issues relating to ordering and receiving pharmacogenomic tests and medications. We found that the process of ordering pharmacogenomic tests is time-consuming, expensive, and complex. Ordering pharmacogenomic tests is quite different across institutions. Even in the same institution, multiple providers can order the test. Once the provider places the order for the pharmacogenomic test, the laboratory receives the request and usually begins testing without knowing how the test will be paid for. Next, the laboratory completes the pharmacogenomic testing and the results of the tests are reported to providers, patients, or placed directly in the medical record. In conclusion, processes related to ordering and obtaining insurance coverage for pharmacogenomic tests varies greatly across institutions and is time-consuming.


Preconception Lifestyle and Cardiovascular Health in the Offspring of Overweight and Obese Women.
Women's lifestyle has important implications for the development and health of their offspring. Yet little is known about the association between women's preconception dietary intake and physical activity with cardiovascular health of the offspring. We therefore examined this association in a group of Dutch women with overweight or obesity (BMI ≥ 29 kg/m2) and infertility, who participated in a 6-month randomized preconception lifestyle intervention trial, and their offspring (n = 46). Preconception dietary intake and physical activity were assessed during the 6-month intervention using a food frequency questionnaire and the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH), respectively. Offspring cardiovascular health (i.e., BMI, waist:height ratio, systolic and diastolic blood pressure, fat and fat free mass, and pulse wave velocity) was measured at age 3-6 years. Multivariable linear regression analyses were used to examine the associations between preconception lifestyle and offspring cardiovascular health. Higher preconception vegetable intake (per 10 g/day) was associated with lower offspring diastolic blood pressure (Z-score: -0.05 (-0.08; -0.01); p = 0.007) and higher preconception fruit intake (per 10 g/day) was associated with lower offspring pulse wave velocity (-0.05 m/s (-0.10; -0.01); p = 0.03). Against our expectations, higher preconception intake of sugary drinks was associated with a higher offspring fat free mass (0.54 kg (0.01; 1.07); p = 0.045). To conclude, preconception dietary intake is associated with offspring health.


Von Willebrand's disease in the year 2003: towards the complete identification of gene defects for correct diagnosis and treatment.
Von Willebrand's disease (VWD) is an autosomally inherited bleeding disorder caused by a deficiency or abnormality of von Willebrand factor (VWF). VWF is a multimeric adhesive protein which plays an important role in primary hemostasis by promoting platelet adhesion to the subendothelium at sites of vascular injury and platelet-platelet interactions in high shear-rate conditions. It is also the carrier of factor VIII (FVIII), thus indirectly contributing to the coagulation process. VWD has a prevalence of about 1% in the general population, but the figure for clinically relevant cases is lower (about 100/million inhabitants). Bleeding manifestations are heterogeneous: mucosal bleeding is typical of all VWD cases but hemarthrosis and hematomas may also be present when FVIII levels are low. Most cases appear to have a partial quantitative deficiency of VWF (type 1 VWD) with variable bleeding tendency, whereas qualitative variants (type 2 VWD), due to a dysfunctional VWF, are clinically more homogeneous. Type 3 VWD is rare and the patients have a moderate to severe bleeding diathesis because of the virtual absence of VWF, and a recessive pattern of inheritance. The diagnosis of VWD, especially type I, may be difficult, because the laboratory phenotype is highly heterogeneous and is confounded by the fact that factors outside the VWF gene (e.g., blood group) influence VWF levels. An array of tests is usually required to characterize the VWD types of the disorder and establish the best treatment modality. The aim of treatment is to correct the dual defect of hemostasis, i.e. abnormal coagulation expressed by low levels of FVIII and abnormal platelet adhesion expressed by the prolonged bleeding time (BT). Desmopressin (DDAVP) is the treatment of choice for type 1 VWD because it corrects the FVIII/VWF levels and the prolonged BT in the majority of cases. In type 3 and in severe forms of type 1 and 2 VWD, DDAVP is not effective and for these patients plasma virally-inactivated concentrates containing FVIII and VWF are the mainstay of treatment. These concentrates are clinically effective and safe, although they do not always correct the BT.


[Molecular mechanisms of neuronal polarity].
Neurons are one of the most highly polarized cells known and are comprised of two structurally and functionally distinct parts, an axon and dendrites. The specification of the axon is thought to depend on its length relative to the other minor processes, which are called immature neurites. Elongation of one of immature neurites is necessary for axon specification. We previously showed that collapsin response mediator protein-2 (CRMP-2) is critical for specifying axon/dendrite fate, possibly by promoting neurite elongation via microtubule assembly. Here, we showed that glycogen synthase kinase-3beta (GSK-3beta) phosphorylated CRMP-2 at Thr-514 and inactivated it. The expression of the nonphosphorylated form of CRMP-2 or inhibition of GSK-3beta induced the formation of multiple axons in hippocampal neurons. The expression of constitutively active GSK-3beta impaired neuronal polarization, whereas the nonphosphorylated form of CRMP-2 counteracted the inhibitory effects of GSK-3beta, indicating that GSK-3beta regulates neuronal polarity through the phosphorylation of CRMP-2. We here reviewed the molecular mechanisms of the axon formation.


Patterning the vertebrate neuraxis.
Neuraxial patterning is a continuous process that extends over a protracted period of development. During gastrulation a crude anteroposterior pattern, detectable by molecular markers, is conferred on the neuroectoderm by signals from the endomesoderm that are largely inseparable from those of neural induction itself. This coarse-grained pattern is subsequently reinforced and refined by diverse, locally acting mechanisms. Segmentation and long-range signaling from organizing centers are prominent among the emerging principles governing regional pattern.


In Vivo Inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke.
A multifunctional microRNA, miR-155, has been recently recognized as an important modulator of numerous biological processes. In our previous in vitro studies, miR-155 was identified as a potential regulator of the endothelial morphogenesis. The present study demonstrates that in vivo inhibition of miR-155 supports cerebral vasculature after experimental stroke. Intravenous injections of a specific miR-155 inhibitor were initiated at 48 h after mouse distal middle cerebral artery occlusion (dMCAO). Microvasculature in peri-infarct area, infarct size, and animal functional recovery were assessed at 1, 2, and 3 weeks after dMCAO. Using in vivo two-photon microscopy, we detected improved blood flow and microvascular integrity in the peri-infarct area of miR-155 inhibitor-injected mice. Electron microscopy revealed that, in contrast to the control group, these animals demonstrated well preserved capillary tight junctions (TJs). Western blot analysis data indicate that improved TJ integrity in the inhibitor-injected animals could be associated with stabilization of the TJ protein ZO-1 and mediated by the miR-155 target protein Rheb. MRI analysis showed significant (34%) reduction of infarct size in miR-155 inhibitor-injected animals at 21 d after dMCAO. Reduced brain injury was confirmed by electron microscopy demonstrating decreased neuronal damage in the peri-infarct area of stroke. Preservation of brain tissue was reflected in efficient functional recovery of inhibitor-injected animals. Based on our findings, we propose that in vivo miR-155 inhibition after ischemia supports brain microvasculature, reduces brain tissue damage, and improves the animal functional recovery. Significance statement: In the present study, we investigated an effect of the in vivo inhibition of a microRNA, miR-155, on brain recovery after experimental cerebral ischemia. To our knowledge, this is the first report describing the efficiency of intravenous anti-miRNA injections in a mouse model of ischemic stroke. The role of miRNAs in poststroke revascularization has been unexplored and in vivo regulation of miRNAs during the subacute phase of stroke has not yet been proposed. Our investigation introduces a new and unexplored approach to cerebral regeneration: regulation of poststroke angiogenesis and recovery through direct modulation of specific miRNA activity. We expect that our findings will lead to the development of novel strategies for regulating neurorestorative processes in the postischemic brain.


The post-birthday world: consequences of temporal landmarks for temporal self-appraisal and motivation.
Much as physical landmarks help structure our representation of space, temporal landmarks such as birthdays and significant calendar dates structure our perception of time, such that people may organize or categorize their lives into "chunks" separated by these markers. Categories on the temporal landscape may vary depending on what landmarks are salient at a given time. We suggest these landmarks have implications for identity and motivation. The present research examined consequences of salient temporal landmarks for perceptions of the self across time and motivation to pursue successful future selves. Studies 1 and 2 show that temporally extended selves are perceived as less connected to, and more dissimilar from, the current self when an intervening landmark event has been made salient. Study 3 addresses the proposed mechanism, demonstrating that intervening landmarks lead people to categorize pre- and postlandmark selves into separate categories more often than when the same time period contains no salient landmarks. Finally, we examined whether landmark-induced mental contrasting of present state and future desired state could increase goal-pursuit motivation (in an effort to bridge the gap between inferior present and better future states). Studies 4-6 demonstrate that landmark-induced discrepancies between current health and hoped-for future health increased participants' motivation to exercise and increased the likelihood that they acted in line with their future-oriented goals.


Toward nanofluids of ultra-high thermal conductivity.
The assessment of proposed origins for thermal conductivity enhancement in nanofluids signifies the importance of particle morphology and coupled transport in determining nanofluid heat conduction and thermal conductivity. The success of developing nanofluids of superior conductivity depends thus very much on our understanding and manipulation of the morphology and the coupled transport. Nanofluids with conductivity of upper Hashin-Shtrikman (H-S) bound can be obtained by manipulating particles into an interconnected configuration that disperses the base fluid and thus significantly enhancing the particle-fluid interfacial energy transport. Nanofluids with conductivity higher than the upper H-S bound could also be developed by manipulating the coupled transport among various transport processes, and thus the nature of heat conduction in nanofluids. While the direct contributions of ordered liquid layer and particle Brownian motion to the nanofluid conductivity are negligible, their indirect effects can be significant via their influence on the particle morphology and/or the coupled transport.


The Vancouver Lung Cancer Risk Prediction Model: Assessment by Using a Subset of the National Lung Screening Trial Cohort.
Purpose To assess the likelihood of malignancy among a subset of nodules in the National Lung Screening Trial (NLST) by using a risk calculator based on nodule and patient characteristics. Materials and Methods All authors received approval for use of NLST data. An institutional review board exemption and a waiver for informed consent were granted to the author with an academic appointment. Nodule characteristics and patient attributes with regard to benign and malignant nodules in the NLST were applied to a nodule risk calculator from a group in Vancouver, Canada. Patient populations and their nodule characteristics were compared between the NLST and Vancouver cohorts. Multiple thresholds were tested to distinguish benign nodules from malignant nodules. An optimized threshold value was used to determine positive and negative predictive values, and a full logistic regression model was applied to the NLST data set. Results Sufficient data were available for 4431 nodules (4315 benign nodules and 116 malignant nodules) from the NLST data set. The NLST and Vancouver data sets differed in that the former included fewer nodules per study, fewer nonsolid nodules, and more nodule spiculation and emphysema. A composite risk score threshold of 10% was determined to be optimal, demonstrating sensitivity, specificity, positive predictive value, and negative predictive value of 85.3%, 93.9%, 27.4%, and 99.6%, respectively. The receiver operating characteristic curve for the full regression model applied to the NLST database demonstrated an area under the receiver operating characteristic curve of 0.963 (95% confidence interval: 0.945, 0.974). Conclusion Application of an NLST data subset to the Vancouver risk calculator yielded a high discriminant value, which supports the use of a risk calculator method as a valuable approach to distinguish between benign and malignant nodules. © RSNA, 2016 Online supplemental material is available for this article.


An Inducible TGF-β2-TGFβR Pathway Modulates the Sensitivity of HNSCC Cells to Tyrosine Kinase Inhibitors Targeting Dominant Receptor Tyrosine Kinases.
The epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of head and neck squamous cell carcinomas (HNSCC), and molecularly targeted therapy against the EGFR with the monoclonal antibody cetuximab modestly increases overall survival in head and neck cancer patients. We hypothesize that co-signaling through additional pathways limits the efficacy of cetuximab and EGFR-specific tyrosine kinase inhibitors (TKIs) in the clinical treatment of HNSCC. Analysis of gene expression changes in HNSCC cell lines treated 4 days with TKIs targeting EGFR and/or fibroblast growth factor receptors (FGFRs) identified transforming growth factor beta 2 (TGF-β2) induction in the three cell lines tested. Measurement of TGF-β2 mRNA validated this observation and extended it to additional cell lines. Moreover, TGF-β2 mRNA was increased in primary patient HNSCC xenografts treated for 4 weeks with cetuximab, demonstrating in vivo relevance of these findings. Functional genomics analyses with shRNA libraries identified TGF-β2 and TGF-β receptors (TGFβRs) as synthetic lethal genes in the context of TKI treatment. Further, direct RNAi-mediated silencing of TGF-β2 inhibited cell growth, both alone and in combination with TKIs. Also, a pharmacological TGFβRI inhibitor similarly inhibited basal growth and enhanced TKI efficacy. In summary, the studies support a TGF-β2-TGFβR pathway as a TKI-inducible growth pathway in HNSCC that limits efficacy of EGFR-specific inhibitors.


Tattoos and tattooing. Part I: History and methodology.
Most medical examiners and pathologists who routinely perform autopsies identify tattoos on a daily basis. However, these dermagraphics generally are given only cursory inspection and description, if at all, although many pathologists photograph particularly unique, unusual, or bizarre examples. From a medicolegal perspective, these permanent skin designs are most often used as identification markers, especially in cases of unknown or questionable identity. The majority of pathologists and other physicians are not familiar with the way in which tattoos are applied, much less the history of this unusual art or the various aspects of tattoos that may provide even more complete information as to how, where, why, and when the tattoos were done. This article, the first of three parts, provides a brief but comprehensive history of tattooing from both the worldwide and Western perspectives, describes how professional tattooing is done, and illustrates the machines involved and the various constituents of the inks that are currently used. The second and third articles will explore the gross and histopathology of tattoos, methods of tattoo removal, medical applications and complications associated with tattoos, psychology and psychopathology of tattoos, and the importance of tattoos in forensic medicine.


Enrichment of processed pseudogene transcripts in L1-ribonucleoprotein particles.
Long INterspersed Elements (LINE-1s, L1s) are responsible for over one million retrotransposon insertions and 8000 processed pseudogenes (PPs) in the human genome. An active L1 encodes two proteins (ORF1p and ORF2p) that bind with L1 RNA and form L1-ribonucleoprotein particles (RNPs). Although it is believed that the RNA-binding property of ORF1p is critical to recruit other mobile RNAs to the RNP, the identity of recruited RNAs is largely unknown. Here, we used crosslinking and immunoprecipitation followed by deep sequencing to identify RNA components of L1-RNPs. Our results show that in addition to retrotransposed RNAs [L1, Alu and SINE-VNTR-Alu (SVA)], L1-RNPs are enriched with cellular mRNAs, which have PPs in the human genome. Using purified L1-RNPs, we show that PP-source RNAs preferentially serve as ORF2p templates in a reverse transcriptase assay. In addition, we find that exogenous ORF2p binds endogenous ORF1p, allowing reverse transcription of the same PP-source RNAs. These data demonstrate that interaction of a cellular RNA with the L1-RNP is an inside track to PP formation.


Structural interdependence in teams: An integrative framework and meta-analysis.
Although interdependence is a central aspect of team design, there has been a lack of clarity regarding the meaning and impact of different forms of interdependence. To provide theoretical clarity and to advance research on team interdependence, we develop an organizing, conceptual framework of interdependence in teams and test it using meta-analysis. We first review and tie together different conceptualizations of interdependence in the literature and illustrate how they converge around 2 major constructs: task interdependence and outcome interdependence. After providing integrative definitions of these forms of interdependence, as well as subdimensions, we then explore the relative effects of task and outcome interdependence on team functioning and performance. Specifically, we propose a pattern of differential effects in which task interdependence is primarily associated with team performance through its effects on task-focused team functioning (i.e., transition/action processes, collective efficacy), whereas outcome interdependence is primarily associated with team performance through its effects on relational team functioning (i.e., interpersonal processes, cohesion). We test these differential effects using a meta-analytic database of 107 independent samples and 7,563 teams. The meta-analytic path model provides strong support for our hypotheses. Implications and future directions for the study of interdependence in work teams are discussed.


Functionality of Two Origins of Replication in Vibrio cholerae Strains With a Single Chromosome.
Chromosomal inheritance in bacteria usually entails bidirectional replication of a single chromosome from a single origin into two copies and subsequent partitioning of one copy each into daughter cells upon cell division. However, the human pathogen Vibrio cholerae and other Vibrionaceae harbor two chromosomes, a large Chr1 and a small Chr2. Chr1 and Chr2 have different origins, an oriC-type origin and a P1 plasmid-type origin, respectively, driving the replication of respective chromosomes. Recently, we described naturally occurring exceptions to the two-chromosome rule of Vibrionaceae: i.e., Chr1 and Chr2 fused single chromosome V. cholerae strains, NSCV1 and NSCV2, in which both origins of replication are present. Using NSCV1 and NSCV2, here we tested whether two types of origins of replication can function simultaneously on the same chromosome or one or the other origin is silenced. We found that in NSCV1, both origins are active whereas in NSCV2 ori2 is silenced despite the fact that it is functional in an isolated context. The ori2 activity appears to be primarily determined by the copy number of the triggering site, crtS, which in turn is determined by its location with respect to ori1 and ori2 on the fused chromosome.


Intelligent Liver Function Testing: Working Smarter to Improve Patient Outcomes in Liver Disease.
Chronic liver disease (CLD) is a significant health problem affecting millions of people worldwide. In Scotland, CLD is a major cause of premature mortality. Liver function tests (LFTs) are a panel of frequently requested blood tests which may indicate liver disease. However, LFTs commonly contain at least one abnormal result, and abnormalities are rarely investigated to the extent recommended by national guidelines. The intelligent Liver Function Testing (iLFT) pathway is a novel, automated system designed to improve early diagnosis of liver disease. Initial abnormal LFT results trigger a cascade of reflexive testing to help identify the cause of any liver dysfunction. Algorithms combine these results with demographic and clinical data (such as patient age, body mass index, and alcohol intake) and fibrosis estimates to produce an electronic diagnosis and management plan. The pilot trial demonstrated that iLFT increased diagnosis of liver disease whilst remaining cost-effective. As such, iLFT has been fully operational across our region (NHS Tayside, Scotland) since August 2018. In the first year, iLFT generated over 2000 diagnoses from 1824 patient samples with an abnormality in the initial LFTs. The majority of these patients could be safely managed in primary care. iLFT allows maximal value to be obtained from liver blood tests across biochemistry, virology, immunology, and hematology with only minor changes to working practices. 'Intelligent', algorithm-led testing pathways break down the barrier between clinical and laboratory medicine and offer solutions to many of the challenges experienced in modern healthcare systems.


Caesarean section to prevent transmission of hepatitis B: a meta-analysis.
Vertical transmission of hepatitis B virus (HBV) occurs in up to 10% to 20% of births. To assess whether Caesarean section, compared with vaginal delivery, prevents HBV transmission. A systematic review and meta-analysis was conducted. Two investigators independently searched PubMed, EMBASE and other databases for relevant studies published between 1988 and 2013. A manual search of relevant topics and major conferences for abstracts was also conducted. Randomized trials, cohort and case-control studies assessing the effect of delivery mode on vertical transmission of HBV were included. Studies assessing antiviral therapy and patients with coinfection were excluded. The primary outcome was HBV transmission rates according to delivery method. Of the 430 studies identified, 10 were included. Caesarean section decreased the odds of HBV transmission by 38% compared with vaginal delivery (OR 0.62 [95% CI 0.40 to 0.98]; P=0.04) based on a random-effects model. Significant heterogeneity among studies was found (I²=63%; P=0.003), which was largely explained by variation in hepatitis B immune globulin (HBIG) administration. Meta-regression showed a significant linear association between the percentage of infants receiving HBIG per study and the log OR (P=0.005), with the least benefit observed in studies with 100% HBIG administration. Subgroup analysis of hepatitis B e-antigen-positive women who underwent Caesarean section did not show a significant reduction in vertical transmission. Caesarean section may protect against HBV transmission; however, convincing benefit could not be demonstrated due to significant study heterogeneity from variable HBIG administration, highlighting the importance of HBIG in HBV prevention. More high-quality studies are needed before any recommendations can be made.


Dental monomers inhibit LPS-induced cytokine release from the macrophage cell line RAW264.7.
Methacrylate monomers have been identified in aqueous extracts of freshly cured dental fillings. The hypothesis tested presently was that low concentrations of triethyleneglycol dimethacrylate (TEGDMA) and 2-hydroxyethyl methacrylate (HEMA) alone or in combination interfere with the LPS-induced release of cytokines from the macrophage cell line RAW264.7. The cells were exposed to 5-200 μM of monomers for 24 h followed by a 24 h combined exposure to monomers and LPS. TEGDMA reduced LPS-induced release of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), whereas HEMA only reduced IL-1β release. Co-exposure to the two monomers indicated an additive effect. Moreover, the reduced cytokine release persisted for 24 h after termination of the monomer exposure. The LPS-induced activation of proteins in pre-transcriptional signaling pathways (CD14, p-ERK1/2, p-p38, p-JNK, p-IκB-α and p-NFκB-p65) was not altered by monomer exposure, neither were the levels of IL-1β and TNF-α mRNA. However, the LPS-induced level of pro-IL-1β was decreased by the monomer treatment. Thus, HEMA and TEGDMA may interfere with post-transcriptional regulation of synthesis and release of these cytokines. Overall, the results suggest that low concentrations of monomers may cause impaired macrophage responses, and that these effects can persist for up to 24 h after exposure.


Early prediction of mortality in isolated head injury patients: a new predictive model.
To construct a predictive model of survival in isolated head injury patients, on the basis of easily available parameters that are independent risk factors for survival outcome. Trauma registry-based study of head injury patients who had no other major extracranial injuries and were not hypotensive at admission. A predictive model of probability of death was constructed using discriminant analysis, on the basis of admission Glasgow Coma Scale (GCS) score, head Abbreviated Injury Score (AIS), age, and mechanism of injury. The study included 7,191 patients with head trauma. The overall correct classification rate of the proposed predictive model was 94.2% as compared with 89.0% of the admission GCS score (p < 0.05) and 92.8% of the head AIS (p < 0.05). The correct classification rate of the predictive model developed for the severe head trauma (GCS score 4-8) patients was 79.9%, as compared with 72.6% using the admission GCS score alone or 75.1% (p < 0.05). A one-page, easy to use table summarizing the predicted mortality on the basis of GCS score, head AIS, mechanism of injury, and age was developed. The proposed model has a significantly better predictive power, especially in severe head trauma, than the extensively used GCS and head AIS. A simple table on the probability of death of a particular patient based on admission GCS score, head AIS, mechanism of injury and age of patient can provide instant information.