A Pilot Randomized Controlled Trial of a Digital Intervention Aimed at Improving Food Purchasing Behavior: The Front-of-Pack Food Labels Impact on Consumer Choice Study.
Most food in the United Kingdom is purchased in supermarkets, and many of these purchases are routinely tracked through supermarket loyalty card data. Using such data may be an effective way to develop remote public health interventions and to measure objectively their effectiveness at changing food purchasing behavior. The Front-of-pack food Labels: Impact on Consumer Choice (FLICC) study is a pilot randomized controlled trial of a digital behavior change intervention. This pilot trial aimed to collect data on recruitment and retention rates and to provide estimates of effect sizes for the primary outcome (healthiness of ready meals and pizzas purchased) to inform a larger trial. The intervention consisted of a website where participants could access tailored feedback on previous purchases of ready meals and pizzas, set goals for behavior change, and model and practice the recommended healthy shopping behavior using traffic light labels. The control consisted of Web-based information on traffic light labeling. Participants were recruited via email from a list of loyalty card holders held by the participating supermarket. All food and drink purchases for the participants for the 6 months before recruitment, during the 6-week intervention period, and during a 12-week washout period were transferred to the research team by the participating supermarket. Healthiness of ready meals and pizzas was measured using a predeveloped scale based solely on the traffic light colors on the foods. Questionnaires were completed at recruitment, end of the intervention, and end of washout to estimate the effect of the intervention on variables that mediate behavior change (eg, belief and intention formation). We recruited 496 participants from an initial email to 50,000 people. Only 3 people withdrew from the study, and purchase data were received for all other participants. A total of 208 participants completed all 3 questionnaires. There was no difference in the healthiness of purchased ready meals and pizzas between the intervention and control arms either during the intervention period (P=.32) or at washout (P=.59). Although the FLICC study did not find evidence of an impact of the intervention on food purchasing behavior, the unique methods used in this pilot trial are informative for future studies that plan to use supermarket loyalty card data in collaboration with supermarket partners. The experience of the trial showcases the possibilities and challenges associated with the use of loyalty card data in public health research. ISRCTN Registry ISRCTN19316955; http://www.isrctn.com/ISRCTN19316955 (Archived by WebCite at http://www.webcitation.org/76IVZ9WjK). RR2-10.1186/s40814-015-0015-1.


Fission product decontamination factors for plutonium separated by PUREX from low-burnup, fast-neutron irradiated depleted UO2.
Experimental investigations to determine fission product separation from actinides (U and Pu) while employing the Plutonium Uranium Recovery by Extraction (PUREX) process to purify plutonium produced in a fast neutron irradiated depleted uranium dioxide (DUO2) target were conducted. The sample was a DUO2 pellet (0.256wt% 235U) irradiated to a low-burnup (4.43±0.31GWd/tHM) that was PUREX processed 538 days after neutron irradiation. Decontamination factors (DF) for the elements U, Mo, Ru, Ce, Sm, Sr, Pm, Eu, Nd, Pd, and Cd were measured with mass spectroscopy in two experiments using 30vol% tri-n-butyl phosphate (TBP) in a kerosene diluent. The first experiment characterized Pu DFs for a single stage extraction and back-extraction, while the second experiment had multiple stages with the goal of achieving greater Pu recovery. The benchtop scale PUREX process had overall Pu recoveries of (83.4±9.5)% and (99.7±4.2)% for the first and second experiments, respectively.


Search for Pair-Produced Resonances Each Decaying into at Least Four Quarks in Proton-Proton Collisions at sqrt[s]=13 TeV.
This Letter presents the results of a search for pair-produced particles of masses above 100 GeV that each decay into at least four quarks. Using data collected by the CMS experiment at the LHC in 2015-2016, corresponding to an integrated luminosity of 38.2 fb^{-1}, reconstructed particles are clustered into two large jets of similar mass, each consistent with four-parton substructure. No statistically significant excess of data over the background prediction is observed in the distribution of average jet mass. Pair-produced squarks with dominant hadronic R-parity-violating decays into four quarks and with masses between 0.10 and 0.72 TeV are excluded at 95% confidence level. Similarly, pair-produced gluinos that decay into five quarks are also excluded with masses between 0.10 and 1.41 TeV at 95% confidence level. These are the first constraints that have been placed on pair-produced particles with masses below 400 GeV that decay into four or five quarks, bridging a significant gap in the coverage of R-parity-violating supersymmetry parameter space.


A druggable secretory protein maturase of Toxoplasma essential for invasion and egress.
Micronemes and rhoptries are specialized secretory organelles that deploy their contents at the apical tip of apicomplexan parasites in a regulated manner. The secretory proteins participate in motility, invasion, and egress and are subjected to proteolytic maturation prior to organellar storage and discharge. Here we establish that Toxoplasma gondii aspartyl protease 3 (ASP3) resides in the endosomal-like compartment and is crucially associated to rhoptry discharge during invasion and to host cell plasma membrane lysis during egress. A comparison of the N-terminome, by terminal amine isotopic labelling of substrates between wild type and ASP3 depleted parasites identified microneme and rhoptry proteins as repertoire of ASP3 substrates. The role of ASP3 as a maturase for previously described and newly identified secretory proteins is confirmed in vivo and in vitro. An antimalarial compound based on a hydroxyethylamine scaffold interrupts the lytic cycle of T. gondii at submicromolar concentration by targeting ASP3.


Circular RNAs in the cardiovascular system.
Until recently considered as rare, circular RNAs (circRNAs) are emerging as important regulators of gene expression. They are ubiquitously expressed and represent a novel branch of the family of non-coding RNAs. Recent investigations showed that circRNAs are regulated in the cardiovascular system and participate in its physiological and pathological development. In this review article, we will provide an overview of the role of circRNAs in cardiovascular health and disease. After a description of the biogenesis of circRNAs, we will summarize what is known of the expression, regulation and function of circRNAs in the cardiovascular system. We will then address some technical aspects of circRNAs research, discussing how artificial intelligence may aid in circRNAs research. Finally, the potential of circRNAs as biomarkers of cardiovascular disease will be addressed and directions for future research will be proposed.


Specific sex drug combinations contribute to the majority of recent HIV seroconversions among MSM in the MACS.
New HIV infections are being observed among men who have sex with men (MSM). Understanding the fusion of risky sexual behaviors, stimulant and erectile dysfunction drug use with HIV seroconversion may provide direction for focused intervention. During the follow-up period (1998-2008), we identified 57 HIV seroconverters among 1667 initially HIV-seronegative men. Time to seroconversion was modeled using Cox proportional hazards regression analysis for 7 combinations of sex drugs (inhaled nitrites or "poppers", stimulants, and erectile dysfunction drugs) used at the current or previous semiannual visit, adjusting for other risk factors including sexual behavior, alcohol and other drugs used, and depression. Model-based adjusted attributable risks were then calculated. The risk of seroconversion increased linearly with the number of unprotected receptive anal sex partners (URASP), with hazard ratios ranging from 1.73 [95% confidence interval (CI): 0.75 to 4.01] for 1 partner, to 4.23 (95% CI: 1.76 to 10.17) for 2-4 partners, and to 14.21 (95% CI: 6.27 to 32.20) for 5+ partners, independent of other risk factors. After adjustment, risks for seroconversion increased from 2.99 (95% CI: 1.02 to 8.76) for men who reported using stimulants only (1 drug) to 8.45 (95% CI: 2.67 to 26.71) for men who reported using all 3 sex drugs. The use of any of the 7 possible sex drug combinations accounted for 63% of the 9-year HIV seroincidence in the Multicenter AIDS Cohort Study. When contributions of increased URASP and combination drug use were analyzed together, the total attributable risk for HIV seroconversion was 74%, with 41% attributable to URASP alone and a residual of 33% due to other direct or indirect effects of sex drug use. Use of poppers, stimulants, and erectile dysfunction drugs increased risk for HIV seroconversion significantly in this cohort. These data reinforce the importance of implementing interventions that target drug reduction as part of comprehensive and efficacious HIV prevention strategies.


Imaging with intermolecular multiple-quantum coherences in solution nuclear magnetic resonance.
A magnetic resonance imaging technique based on intermolecular multiple-quantum coherences in solution (the correlated spectroscopy revamped by asymmetric z gradient echo detection or CRAZED experiment) is described here. Correlations between spins in different molecules were detected by magnetic-field gradient pulses. In order for a correlation to yield an observable signal, the separation between the two spins must be within a narrow band that depends on the area of the gradient pulses. The separation can be tuned from less than 10 micrometers to more than 1 millimeter, a convenient range for many applications.


Prokaryotic homologs of Argonaute proteins are predicted to function as key components of a novel system of defense against mobile genetic elements.
In eukaryotes, RNA interference (RNAi) is a major mechanism of defense against viruses and transposable elements as well of regulating translation of endogenous mRNAs. The RNAi systems recognize the target RNA molecules via small guide RNAs that are completely or partially complementary to a region of the target. Key components of the RNAi systems are proteins of the Argonaute-PIWI family some of which function as slicers, the nucleases that cleave the target RNA that is base-paired to a guide RNA. Numerous prokaryotes possess the CRISPR-associated system (CASS) of defense against phages and plasmids that is, in part, mechanistically analogous but not homologous to eukaryotic RNAi systems. Many prokaryotes also encode homologs of Argonaute-PIWI proteins but their functions remain unknown. We present a detailed analysis of Argonaute-PIWI protein sequences and the genomic neighborhoods of the respective genes in prokaryotes. Whereas eukaryotic Ago/PIWI proteins always contain PAZ (oligonucleotide binding) and PIWI (active or inactivated nuclease) domains, the prokaryotic Argonaute homologs (pAgos) fall into two major groups in which the PAZ domain is either present or absent. The monophyly of each group is supported by a phylogenetic analysis of the conserved PIWI-domains. Almost all pAgos that lack a PAZ domain appear to be inactivated, and the respective genes are associated with a variety of predicted nucleases in putative operons. An additional, uncharacterized domain that is fused to various nucleases appears to be a unique signature of operons encoding the short (lacking PAZ) pAgo form. By contrast, almost all PAZ-domain containing pAgos are predicted to be active nucleases. Some proteins of this group (e.g., that from Aquifex aeolicus) have been experimentally shown to possess nuclease activity, and are not typically associated with genes for other (putative) nucleases. Given these observations, the apparent extensive horizontal transfer of pAgo genes, and their common, statistically significant over-representation in genomic neighborhoods enriched in genes encoding proteins involved in the defense against phages and/or plasmids, we hypothesize that pAgos are key components of a novel class of defense systems. The PAZ-domain containing pAgos are predicted to directly destroy virus or plasmid nucleic acids via their nuclease activity, whereas the apparently inactivated, PAZ-lacking pAgos could be structural subunits of protein complexes that contain, as active moieties, the putative nucleases that we predict to be co-expressed with these pAgos. All these nucleases are predicted to be DNA endonucleases, so it seems most probable that the putative novel phage/plasmid-defense system targets phage DNA rather than mRNAs. Given that in eukaryotic RNAi systems, the PAZ domain binds a guide RNA and positions it on the complementary region of the target, we further speculate that pAgos function on a similar principle (the guide being either DNA or RNA), and that the uncharacterized domain found in putative operons with the short forms of pAgos is a functional substitute for the PAZ domain. The hypothesis that pAgos are key components of a novel prokaryotic immune system that employs guide RNA or DNA molecules to degrade nucleic acids of invading mobile elements implies a functional analogy with the prokaryotic CASS and a direct evolutionary connection with eukaryotic RNAi. The predictions of the hypothesis including both the activities of pAgos and those of the associated endonucleases are readily amenable to experimental tests.


Functional morphometric analysis of the furcula in mesozoic birds.
The furcula displays enormous morphological and structural diversity. Acting as an important origin for flight muscles involved in the downstroke, the form of this element has been shown to vary with flight mode. This study seeks to clarify the strength of this form-function relationship through the use of eigenshape morphometric analysis coupled with recently developed phylogenetic comparative methods (PCMs), including phylogenetic Flexible Discriminant Analysis (pFDA). Additionally, the morphospace derived from the furculae of extant birds is used to shed light on possible flight adaptations of Mesozoic fossil taxa. While broad conclusions of earlier work are supported (U-shaped furculae are associated with soaring, strong anteroposterior curvature with wing-propelled diving), correlations between form and function do not appear to be so clear-cut, likely due to the significantly larger dataset and wider spectrum of flight modes sampled here. Interclavicular angle is an even more powerful discriminator of flight mode than curvature, and is positively correlated with body size. With the exception of the close relatives of modern birds, the ornithuromorphs, Mesozoic taxa tend to occupy unique regions of morphospace, and thus may have either evolved unfamiliar flight styles or have arrived at similar styles through divergent musculoskeletal configurations.


Efficient expansion of global protected areas requires simultaneous planning for species and ecosystems.
The Convention on Biological Diversity (CBD)'s strategic plan advocates the use of environmental surrogates, such as ecosystems, as a basis for planning where new protected areas should be placed. However, the efficiency and effectiveness of this ecosystem-based planning approach to adequately capture threatened species in protected area networks is unknown. We tested the application of this approach in Australia according to the nation's CBD-inspired goals for expansion of the national protected area system. We set targets for ecosystems (10% of the extent of each ecosystem) and threatened species (variable extents based on persistence requirements for each species) and then measured the total land area required and opportunity cost of meeting those targets independently, sequentially and simultaneously. We discover that an ecosystem-based approach will not ensure the adequate representation of threatened species in protected areas. Planning simultaneously for species and ecosystem targets delivered the most efficient outcomes for both sets of targets, while planning first for ecosystems and then filling the gaps to meet species targets was the most inefficient conservation strategy. Our analysis highlights the pitfalls of pursuing goals for species and ecosystems non-cooperatively and has significant implications for nations aiming to meet their CBD mandated protected area obligations.


Multisite tumor sampling enhances the detection of intratumor heterogeneity at all different temporal stages of tumor evolution.
Intratumor heterogeneity (ITH) is an inherent process of tumor development that has received much attention in previous years, as it has become a major obstacle for the success of targeted therapies. ITH is also temporally unpredictable across tumor evolution, which makes its precise characterization even more problematic since detection success depends on the precise temporal snapshot at which ITH is analyzed. New and more efficient strategies for tumor sampling are needed to overcome these difficulties which currently rely entirely on the pathologist's interpretation. Recently, we showed that a new strategy, the multisite tumor sampling, works better than the routine sampling protocol for the ITH detection when the tumor time evolution was not taken into consideration. Here, we extend this work and compare the ITH detections of multisite tumor sampling and routine sampling protocols across tumor time evolution, and in particular, we provide in silico analyses of both strategies at early and late temporal stages for four different models of tumor evolution (linear, branched, neutral, and punctuated). Our results indicate that multisite tumor sampling outperforms routine protocols in detecting ITH at all different temporal stages of tumor evolution. We conclude that multisite tumor sampling is more advantageous than routine protocols in detecting intratumor heterogeneity.


Markov State Models: From an Art to a Science.
Markov state models (MSMs) are a powerful framework for analyzing dynamical systems, such as molecular dynamics (MD) simulations, that have gained widespread use over the past several decades. This perspective offers an overview of the MSM field to date, presented for a general audience as a timeline of key developments in the field. We sequentially address early studies that motivated the method, canonical papers that established the use of MSMs for MD analysis, and subsequent advances in software and analysis protocols. The derivation of a variational principle for MSMs in 2013 signified a turning point from expertise-driving MSM building to a systematic, objective protocol. The variational approach, combined with best practices for model selection and open-source software, enabled a wide range of MSM analysis for applications such as protein folding and allostery, ligand binding, and protein-protein association. To conclude, the current frontiers of methods development are highlighted, as well as exciting applications in experimental design and drug discovery.


Xerostomia: diagnosis and management.
Xerostomia, or dry mouth, is a common complaint that may be caused by several conditions, which include side effects of a wide variety of drugs, such as antidepressants, therapeutic radiation to the head and neck, dehydration, diabetes, and diseases involving salivary glands, such as Sjögren's syndrome. The complaint of dry mouth may or may not be associated with decreased salivary gland function. Individuals with xerostomia complain of problems with eating, speaking, swallowing, and wearing dentures. Some people also complain of salivary gland enlargement or changes in taste. Lack of saliva may predispose one to oral infections, such as candidiasis, and increase the risk of dental caries. Management of the individual patient with xerostomia includes assessment of salivary gland function, replacement therapy, and prevention of caries and oral candidiasis. Early recognition and management of xerostomia may prevent devastating dental disease and help to improve the quality of life.


Serum Iron Protects from Renal Postischemic Injury.
Renal transplants remain a medical challenge, because the parameters governing allograft outcome are incompletely identified. Here, we investigated the role of serum iron in the sterile inflammation that follows kidney ischemia-reperfusion injury. In a retrospective cohort study of renal allograft recipients (n=169), increased baseline levels of serum ferritin reliably predicted a positive outcome for allografts, particularly in elderly patients. In mice, systemic iron overload protected against renal ischemia-reperfusion injury-associated sterile inflammation. Furthermore, chronic iron injection in mice prevented macrophage recruitment after inflammatory stimuli. Macrophages cultured in high-iron conditions had reduced responses to Toll-like receptor-2, -3, and -4 agonists, which associated with decreased reactive oxygen species production, increased nuclear localization of the NRF2 transcription factor, increased expression of the NRF2-related antioxidant response genes, and limited NF-κB and proinflammatory signaling. In macrophage-depleted animals, the infusion of macrophages cultured in high-iron conditions did not reconstitute AKI after ischemia-reperfusion, whereas macrophages cultured in physiologic iron conditions did. These findings identify serum iron as a critical protective factor in renal allograft outcome. Increasing serum iron levels in patients may thus improve prognosis of renal transplants.


Subset of Cortical Layer 6b Neurons Selectively Innervates Higher Order Thalamic Nuclei in Mice.
The thalamus receives input from 3 distinct cortical layers, but input from only 2 of these has been well characterized. We therefore investigated whether the third input, derived from layer 6b, is more similar to the projections from layer 6a or layer 5. We studied the projections of a restricted population of deep layer 6 cells ("layer 6b cells") taking advantage of the transgenic mouse Tg(Drd1a-cre)FK164Gsat/Mmucd (Drd1a-Cre), that selectively expresses Cre-recombinase in a subpopulation of layer 6b neurons across the entire cortical mantle. At P8, 18% of layer 6b neurons are labeled with Drd1a-Cre::tdTomato in somatosensory cortex (SS), and some co-express known layer 6b markers. Using Cre-dependent viral tracing, we identified topographical projections to higher order thalamic nuclei. VGluT1+ synapses formed by labeled layer 6b projections were found in posterior thalamic nucleus (Po) but not in the (pre)thalamic reticular nucleus (TRN). The lack of TRN collaterals was confirmed with single-cell tracing from SS. Transmission electron microscopy comparison of terminal varicosities from layer 5 and layer 6b axons in Po showed that L6b varicosities are markedly smaller and simpler than the majority from L5. Our results suggest that L6b projections to the thalamus are distinct from both L5 and L6a projections.


Hypersensitive termination of the hypoxic response by a disordered protein switch.
The cellular response to hypoxia is critical for cell survival and is fine-tuned to allow cells to recover from hypoxic stress and adapt to heterogeneous or fluctuating oxygen levels. The hypoxic response is mediated by the α-subunit of the transcription factor HIF-1 (HIF-1α), which interacts through its intrinsically disordered C-terminal transactivation domain with the TAZ1 (also known as CH1) domain of the general transcriptional coactivators CBP and p300 to control the transcription of critical adaptive genes. One such gene encodes CITED2, a negative feedback regulator that attenuates HIF-1 transcriptional activity by competing for TAZ1 binding through its own disordered transactivation domain. Little is known about the molecular mechanism by which CITED2 displaces the tightly bound HIF-1α from their common cellular target. The HIF-1α and CITED2 transactivation domains bind to TAZ1 through helical motifs that flank a conserved LP(Q/E)L sequence that is essential for negative feedback regulation. Here we show that human CITED2 displaces HIF-1α by forming a transient ternary complex with TAZ1 and HIF-1α and competing for a shared binding site through its LPEL motif, thus promoting a conformational change in TAZ1 that increases the rate of HIF-1α dissociation. Through allosteric enhancement of HIF-1α release, CITED2 activates a highly responsive negative feedback circuit that rapidly and efficiently attenuates the hypoxic response, even at modest CITED2 concentrations. This hypersensitive regulatory switch is entirely dependent on the unique flexibility and binding properties of these intrinsically disordered proteins and probably exemplifies a common strategy used by the cell to respond rapidly to environmental signals.


Characterization and comparison of disulfide linkages and scrambling patterns in therapeutic monoclonal antibodies: using LC-MS with electron transfer dissociation.
The disulfides in three monoclonal antibodies (mAb), the anti-HER2, anti-CD11a, and GLP-1 with IgG4-Fc fusion protein, were completely mapped by LC-MS with the combination of electron-transfer dissociation (ETD) and collision induced dissociation (CID) fragmentation. In addition to mapping the 4 inter- and 12 intrachain disulfides (total 16), the identification of scrambled disulfides in degraded samples (heat-stress) was achieved. The scrambling was likely attributed to an initial breakage between the light (Cys 214) and heavy (Cys 223) chains in anti-HER2, with the same observation found in a similar therapeutic mAb, anti-CD11a. On the other hand, the fusion antibody, with no light chain but containing only two heavy chains, generated much less scrambling under the same heat-stressed conditions. The preferred sites of scrambling were identified, such as the intrachain disulfide for CxxC in the heavy chain, and the C194 of the heavy chain pairing with the terminal Cys residue (C214) in the light chain. The interchain disulfides between the light and heavy chains were weaker than the interchain disulfides between the two heavy chains. The relative high abundance ions observed in ETD provided strong evidence for the linked peptide information, which was particularly useful for the identification of the scrambled disulfides. The use of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) helped the separation of these misfolded proteins for the determination of scrambled disulfide linkages. This methodology is useful for comparison of disulfide stability generated from different structural designs and providing a new way to determine the scrambling patterns, which could be applied for those seeking to determine unknown disulfide linkages.


Tea, but not coffee consumption, is associated with components of arterial pressure. The Observation of Cardiovascular Risk Factors study in Luxembourg.
There is uncertainty regarding the impact of tea and coffee consumption on arterial blood pressure. The present study aimed to examine the association between blood pressure (BP) components, namely, systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure (PP), and tea or coffee consumption, taking into account simultaneous consumption. The study population was derived from a national cross-sectional stratified sample of 1352 individuals aged 18 to 69 years, recruited between November 2007 and January 2009 to participate in the Observation of Cardiovascular Risk Factors in Luxembourg study. We hypothesized that greater tea consumption would be independently associated with lower BP. Tea and coffee consumptions in deciliters per day were obtained from a semiquantitative food frequency questionnaire. Participants were classified into 3 groups: nonconsumers, ≤3-dL/d consumers, and >3-dL/d consumers of each beverage separately. After exclusion of subjects taking antihypertensive medications, several general linear models were performed to investigate the independent relationship between tea/coffee consumption and BP components. Tea consumers (36.3%) were more likely to be younger women, nonsmokers, with better cardiometabolic profiles, and less frequent chronic pathologies, whereas the reverse was true for coffee consumers (88%). Greater tea consumption was associated with lower SBP and PP values, after adjustment for age, sex, education, lifestyle, and dietary confounding factors, including coffee drinking. No association between BP components and coffee consumption was observed. Daily consumption of 1 dL of tea was associated with a significant reduction of SBP by 0.6 mm Hg and PP by 0.5 mm Hg. Given the widespread consumption of tea and coffee throughout the world, together with the major cardiovascular disease risk, our findings have important implications for human health.


On the Mechanism of Action of Anti-Inflammatory Activity of Hypericin: An In Silico Study Pointing to the Relevance of Janus Kinases Inhibition.
St. John's Wort (Hypericum perforatum L.) flowers are commonly used in ethnomedical preparations with promising outcomes to treat inflammation both per os and by topical application. However, the underlying molecular mechanisms need to be described toward a rational, evidence-based, and reproducible use. For this purpose, the aptitude of the prominent Hypericum metabolite hypericin was assessed, along with that of its main congeners, to behave as an inhibitor of janus kinase 1, a relevant enzyme in inflammatory response. It was used a molecular modeling approach relying on docking simulations, pharmacophoric modeling, and molecular dynamics to estimate the capability of molecules to interact and persist within the enzyme pocket. Our results highlighted the capability of hypericin, and some of its analogues and metabolites, to behave as ATP-competitive inhibitor providing: (i) a likely mechanistic elucidation of anti-inflammatory activity of H. perforatum extracts containing hypericin and related compounds; and (ii) a rational-based prioritization of H. perforatum components to further characterize their actual effectiveness as anti-inflammatory agents.


Platelet function in clinically healthy cats and cats with hypertrophic cardiomyopathy: analysis using the Platelet Function Analyzer-100.
There is currently no simple analytical tool for the evaluation of hypercoagulability in cats. The Platelet Function Analyzer-100 (PFA-100; Dade Behring Inc., Deerfield, IL, USA) is a bench-top machine that evaluates platelet function by measuring closure time (CT) in citrated whole blood under high shear conditions. We hypothesized that cats with hypertrophic cardiomyopathy (HCM) have up-regulated platelet function, which shortens their CT and increases their risk for thromboembolic events. The goals of this study were to: (1) establish a feline reference interval for CT using the PFA-100, (2) measure CT in blood from cats with HCM, and (3) determine if there is a measurable difference between the CT of healthy cats compared with cats with HCM. Citrated blood samples from 42 clinically healthy cats and 30 cats with HCM were analyzed according to manufacturer's specifications. CT was measured in triplicate and the mean value was used for analysis. Transformed data were compared between clinically healthy cats and cats with HCM using a Student's t-test, and among cats with mild, moderate, or severe HCM using ANOVA. The median CT of clinically healthy cats was 64 seconds (range 43-176 seconds). The median CT of cats with HCM was 74 seconds (range 48-197 seconds). There was no significant difference in CT between cats with HCM and clinically healthy cats. There also were no significant differences in cats with mild, moderate, or severe HCM. A feline reference interval for PFA-100 CT will be useful in future studies of platelet function in cats. Cats with HCM do not have shorter CTs when compared with clinically healthy cats.


Effect of polyphenols from coffee and grape on gene expression in myoblasts.
Coffee and grape contain various bioactive compounds like polyphenols that may exert beneficial effects, especially antioxidant activity, on human health upon consumption. However, the molecular mechanisms through which these effects are achieved are not fully elucidated. Thus, in the present study in order to investigate these mechanisms, a whole genome expression DNA microarray analysis was carried out in myoblasts treated with polyphenols of coffee and grape pomace at concentrations that improved the redox status. Grape was composed of catechin, epicatechin, cyanidin, malvidin, delphinidin, petunidin, myrtillin, kuromanin, oenin, peonidin, quercetin, gallic acid and caftaric acid as LC-MS revealed, with a total polyphenolic content (TPC) of 648 mg of gallic acid equivalents/g of dry matter. Coffee had a TPC of 42.61 mg GAE/g coffee and was composed of 3-chlorogenic acid (16.61 mg/g), 4- and 5-chlorogenic acids (13.62 mg/g), as UHPLC-HRMS revealed. According to the results, grape polyphenols altered mainly the expression of cytoskeleton and differentiation-associated genes, while coffee compounds had a more profound effect, on the expression levels of many metabolic and antioxidant genes possibly through the nuclear factor (erythroid-derived 2) like-2 (Nrf2) pathway.


External validation of Medicare claims codes for digital mammography and computer-aided detection.
While Medicare claims are a potential resource for clinical mammography research or quality monitoring, the validity of key data elements remains uncertain. Claims codes for digital mammography and computer-aided detection (CAD), for example, have not been validated against a credible external reference standard. We matched Medicare mammography claims for women who received bilateral mammograms from 2003 to 2006 to corresponding mammography data from the Breast Cancer Surveillance Consortium (BCSC) registries in four U.S. states (N = 253,727 mammograms received by 120,709 women). We assessed the accuracy of the claims-based classifications of bilateral mammograms as either digital versus film and CAD versus non-CAD relative to a reference standard derived from BCSC data. Claims data correctly classified the large majority of film and digital mammograms (97.2% and 97.3%, respectively), yielding excellent agreement beyond chance (κ = 0.90). Claims data correctly classified the large majority of CAD mammograms (96.6%) but a lower percentage of non-CAD mammograms (86.7%). Agreement beyond chance remained high for CAD classification (κ = 0.83). From 2003 to 2006, the predictive values of claims-based digital and CAD classifications increased as the sample prevalences of each technology increased. Medicare claims data can accurately distinguish film and digital bilateral mammograms and mammograms conducted with and without CAD. The validity of Medicare claims data regarding film versus digital mammography and CAD suggests that these data elements can be useful in research and quality improvement.


West Berkshire perineal management trial: three year follow up.
Women who had participated in a randomised controlled trial of policies of restricted (10%) versus liberal (51%) episiotomy during spontaneous vaginal delivery were recontacted by postal questionnaire three years after delivery. Altogether 674 out of 1000 responded, and there was no evidence of a differential response rate between the two trial groups. Similar numbers of women in the two groups reported further deliveries, almost all of which had been vaginal and spontaneous. Fewer women allocated to restrictive use of episiotomy required perineal suturing after subsequent delivery, but this difference was not significant. Pain during sexual intercourse and incontinence of urine were equally reported in the two groups. The similarity in incontinence rates persisted when severity, type of incontinence, and subsequent deliveries were taken into account. Liberal use of episiotomy does not seem to prevent urinary incontinence or increase long term dyspareunia.


Testosterone replacement therapy for treatment refractory cluster headache.
To describe the clinical characteristics and laboratory findings of cluster headache patients whose headaches responded to testosterone replacement therapy. Current evidence points to hypothalamic dysfunction, with increased metabolic hyperactivity in the region of the suprachiasmatic nucleus, as being important in the genesis of cluster headaches. This is clinically borne out in the circadian and diurnal behavior of these headaches. For years it has been recognized that male cluster headache patients appear overmasculinized. Recent neuroendocrine and sleep studies now point to an association between gonadotropin and corticotropin levels and hypothalamically entrained pineal secretion of melatonin. Seven male and 2 female patients, seen between July 2004 and February 2005, and between the ages of 32 and 56, are reported with histories of treatment resistant cluster headaches accompanied by borderline low or low serum testosterone levels. The patients failed to respond to individually tailored medical regimens, including melatonin doses of 12 mg a day or higher, high flow oxygen, maximally tolerated verapamil, antiepileptic agents, and parenteral serotonin agonists. Seven of the 9 patients met 2004 International Classification for the Diagnosis of Headache criteria for chronic cluster headaches; the other 2 patients had episodic cluster headaches of several months duration. After neurological and physical examination all patients had laboratory investigations including fasting lipid panel, PSA (where indicated), LH, FSH, and testosterone levels (both free and total). All 9 patients demonstrated either abnormally low or low, normal testosterone levels. After supplementation with either pure testosterone in 5 of 7 male patients or combination testosterone/estrogen therapy in both female patients, the patients achieved cluster headache freedom for the first 24 hours. Four male chronic cluster patients, all with abnormally low testosterone levels, achieved remission. Abnormal testosterone levels in patients with episodic or chronic cluster headaches refractory to maximal medical management may predict a therapeutic response to testosterone replacement therapy. In the described cases, diurnal variation of attacks, a seasonal cluster pattern, and previous, transient responsiveness to melatonin therapy pointed to the hypothalamus as the site of neurological dysfunction. Prospective studies pairing hormone levels and polysomnographic data are needed.


Label free detection of nucleic acids by modulating nanochannel surfaces.
We develop surface-modified 100 nm silica nanofluidic channels that change in measured conductivity upon exposure to single- or double-stranded DNA. Through careful monitoring of both electromigrative and advective current in the channel, we can detect nanomolar concentrations of DNA. These results can be exploited for inexpensive, all-electronic DNA sensors.


Effects of exercise training and detraining in patients with fibromyalgia syndrome: a 3-yr longitudinal study.
This study aimed to evaluate the immediate effects of a 6-mo combined exercise program on quality-of-life, physical function, depression, and aerobic capacity in women with fibromyalgia syndrome and to determine the impact of repeated delivery of the intervention. Forty-one women with fibromyalgia were randomly assigned to a training group (EG; n = 21) and a control group (CG; n = 20). Quality-of-life and physical function were assessed using the 36-item Short-Form Health Survey (SF-36) and the Fibromyalgia Impact Questionnaire, and depression was measured using the Beck Depression Inventory. Physical fitness was measured using the 6-min Walk Test. Outcomes were assessed at baseline and after each 6-mo intervention, which was delivered over 30 mos (6 mos of training and 6 mos of detraining). After a 6-mo combined exercise program, there was a significant improvement in the Fibromyalgia Impact Questionnaire (P < 0.0005) for the training group over the control group. Repeated-measures analysis of variance across all time points demonstrated significant main effects for time for the Fibromyalgia Impact Questionnaire, SF-36, Beck Depression Inventory and the 6-min Walk Test, but there were no between-group interaction effects. For the EG, there were significant within-group changes in the Fibromyalgia Impact Questionnaire, SF-36, and Beck Depression Inventory at the final time point; however, there were no within-group changes for the control group. Improvement achieved for the training group were maintained during the detraining period. A long-term exercise program can produce immediate improvements in key health domains in women with fibromyalgia. The benefits achieved with regular training can be maintained for 30 mos. The lack of difference between groups over time may be caused by attrition and consequent lack of power at the final time point.


Establishment of a CpG island microarray for analyses of genome-wide DNA methylation in Chinese hamster ovary cells.
Optimizing productivity and growth rates of recombinant Chinese hamster ovary (CHO) cells requires insight into the regulation of cellular processes. In this regard, the elucidation of the epigenetic process of DNA methylation, known to influence transcription by a differential occurrence in CpG islands in promoter regions, is increasingly gaining importance. However, DNA methylation has not yet been investigated on a genomic scale in CHO cells and suitable tools have not existed until now. Based on the genomic and transcriptomic CHO data currently available, we developed a customized oligonucleotide microarray covering 19598 CpG islands (89 % of total bioinformatically identified CpG islands) in the CHO genome. We applied our CHO-specific CpG island microarray to investigate the effect of butyrate treatment on differential DNA methylation in CHO cultures in a time-dependent approach. Supplementation of butyrate is known to enhance cell specific productivities in CHO cells and leads to alterations of epigenetic silencing events. Gene ontology clusters regarding, e.g., chromatin modification or DNA repair, were significantly overrepresented 24 h after butyrate addition. Functional classifications furthermore indicated that several major signaling systems such as the Wnt/β-catenin pathway were affected by butyrate treatment. Our novel CHO-specific CpG island microarray will provide valuable information in future studies of cellular processes associated with productivity and product characteristics.


Faculty development for informatics: education working group workshop on objectives, methods, and assessment in informatics education.
Biomedical informatics is maturing and growing rapidly as a discipline. There is an increasingly recognized need to expand the biomedical and health informatics workforce, and an expanding array of educational opportunities and training programs, addressing the needs of learners from a wide array of disciplines, at multiple levels of expertise. On the horizon are new forms of certification, and ongoing efforts exist to define the competencies that are needed in the various roles that biomedical and health informatics professionals will occupy. In the midst of all this, an unmet need exists for faculty development. Who will train the thousands of learners expected to enter our field? Who will train the trainers?


A Nonredundant Phosphopantetheinyl Transferase, PptA, Is a Novel Antifungal Target That Directs Secondary Metabolite, Siderophore, and Lysine Biosynthesis in Aspergillus fumigatus and Is Critical for Pathogenicity.
Secondary metabolites are key mediators of virulence for many pathogens. Aspergillus fumigatus produces a vast array of these bioactive molecules, the biosynthesis of which is catalyzed by nonribosomal peptide synthetases (NRPSs) or polyketide synthases (PKSs). Both NRPSs and PKSs harbor carrier domains that are primed for acceptance of secondary metabolic building blocks by a phosphopantetheinyl transferase (P-pant). The A. fumigatus P-pant PptA has been shown to prime the putative NRPS Pes1 in vitro and has an independent role in lysine biosynthesis; however, its role in global secondary metabolism and its impact on virulence has not been described. Here, we demonstrate that PptA has a nonredundant role in the generation of the vast majority of detectable secondary metabolites in A. fumigatus, including the immunomodulator gliotoxin, the siderophores triacetylfusarinine C (TAFC) and ferricrocin (FC), and dihydroxy naphthalene (DHN)-melanin. We show that both the lysine and iron requirements of a pptA null strain exceed those freely available in mammalian tissues and that loss of PptA renders A. fumigatus avirulent in both insect and murine infection models. Since PptA lacks similarity to its mammalian orthologue, we assert that the combined role of this enzyme in both primary and secondary metabolism, encompassing multiple virulence determinants makes it a very promising antifungal drug target candidate. We further exemplify this point with a high-throughput fluorescence polarization assay that we developed to identify chemical inhibitors of PptA function that have antifungal activity.IMPORTANCE Fungal diseases are estimated to kill between 1.5 and 2 million people each year, which exceeds the global mortality estimates for either tuberculosis or malaria. Only four classes of antifungal agents are available to treat invasive fungal infections, and all suffer pharmacological shortcomings, including toxicity, drug-drug interactions, and poor bioavailability. There is an urgent need to develop a new class of drugs that operate via a novel mechanism of action. We have identified a potential drug target, PptA, in the fungal pathogen Aspergillus fumigatus PptA is required to synthesize the immunotoxic compound gliotoxin, DHN-melanin, which A. fumigatus employs to evade detection by host cells, the amino acid lysine, and the siderophores TAFC and FC, which A. fumigatus uses to scavenge iron. We show that strains lacking the PptA enzyme are unable to establish an infection, and we present a method which we use to identify novel antifungal drugs that inactivate PptA.


Hemoglobin A1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the American College of Physicians.
The American College of Physicians developed this guidance statement to guide clinicians in selecting targets for pharmacologic treatment of type 2 diabetes. The National Guideline Clearinghouse and the Guidelines International Network library were searched (May 2017) for national guidelines, published in English, that addressed hemoglobin A1c (HbA1c) targets for treating type 2 diabetes in nonpregnant outpatient adults. The authors identified guidelines from the National Institute for Health and Care Excellence and the Institute for Clinical Systems Improvement. In addition, 4 commonly used guidelines were reviewed, from the American Association of Clinical Endocrinologists and American College of Endocrinology, the American Diabetes Association, the Scottish Intercollegiate Guidelines Network, and the U.S. Department of Veterans Affairs and Department of Defense. The AGREE II (Appraisal of Guidelines for Research and Evaluation II) instrument was used to evaluate the guidelines. Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients' preferences, patients' general health and life expectancy, treatment burden, and costs of care. Clinicians should aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes. Clinicians should consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%. Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population.


Linear mixed models to handle missing at random data in trial-based economic evaluations.
Trial-based cost-effectiveness analyses (CEAs) are an important source of evidence in the assessment of health interventions. In these studies, cost and effectiveness outcomes are commonly measured at multiple time points, but some observations may be missing. Restricting the analysis to the participants with complete data can lead to biased and inefficient estimates. Methods, such as multiple imputation, have been recommended as they make better use of the data available and are valid under less restrictive Missing At Random (MAR) assumption. Linear mixed effects models (LMMs) offer a simple alternative to handle missing data under MAR without requiring imputations, and have not been very well explored in the CEA context. In this manuscript, we aim to familiarize readers with LMMs and demonstrate their implementation in CEA. We illustrate the approach on a randomized trial of antidepressants, and provide the implementation code in R and Stata. We hope that the more familiar statistical framework associated with LMMs, compared to other missing data approaches, will encourage their implementation and move practitioners away from inadequate methods.


Current practices, barriers and enablers for advance care planning among healthcare workers of aged care facilities in western New South Wales, Australia.
Advance care planning (ACP) and advance care directives (ACDs) play a vital role in preparing for end-of-life care. However, current literature suggests that uptake of ACP and ACDs in rural Australia is low, which may contribute to lower quality care for the older rural population, as patients' end-of-life wishes may not be recognised and acknowledged. This study aims to provide a current perspective on the attitudes and practices of healthcare workers from residential aged care facilities towards ACP and ACDs in the central west, far west and Orana regions of New South Wales, Australia. This was a mixed-methods study incorporating anonymous survey and individual interviews. Healthcare workers from 12 residential aged care facilities within the studied region completed surveys (n=109). The 40-item survey assessed participant demographics, training and experience with ACP and ACD, attitudes towards ACP and ACDs, and barriers and facilitators towards the use of ACP and ACDs in their organisation. Five participants were interviewed to explore these issues in more depth. Almost three-quarters (71%) of respondents thought that ACP is necessary while almost half (48%) were involved with >5 ACDs in the past 12 months. Formal training was seen as beneficial by most (81%) but the importance of practical experience was also acknowledged. No statistically significant differences were found in attitudes between those with 5 years of experience. Avoidance of unnecessary resuscitation was a consistent theme in all interviews and the potential of a nurse-led model of delivery was identified. Patient factors such as decreased capacity to make informed decisions were identified as barriers that could be circumvented by pre-emptive implementation of ACP discussion. The rural setting was identified as a facilitator due to a supportive community, which helped to mitigate barriers such as limited staffing. Attitudes towards ACP in rural New South Wales are highly positive. The rural setting is a facilitator to ACP, and ACDs are approached in a multidisciplinary fashion. Further training is an identified need although on-the-ground experience may be more beneficial.


Immunologic characterization of CD7-deficient mice.
Human CD7 is an Ig superfamily molecule that is expressed on mature T and NK lymphocytes. Although in vitro studies have suggested a role for CD7 in lymphoid development and function, the exact function of CD7 in vivo has remained elusive. One patient has been reported with SCID syndrome attributed to CD7 deficiency. To study in vivo functions of CD7, we have generated CD7-deficient mice and assessed their lymphoid development and function. CD7-deficient mice were viable, had normal peripheral blood and spleen lymphocyte numbers, and had normal specific Ab responses with Ag-driven Ig isotype switching. Thymocyte numbers were normal in 4-wk-old, 6-mo-old, and 1-yr-old CD7-deficient mice, but in 3-mo-old CD7-deficient mice, total thymocyte numbers were significantly increased by 60% (p < 0.02) compared with normal age-matched +/+ littermates. CD7-deficient splenocytes proliferated normally in response to various mitogens, including PHA, anti-CD3, Con A, and LPS. While NK cell numbers and cytolytic activity to YAC targets were normal, CD7-deficient mice had lower Ag-induced MHC class I-restricted CTL activity against OVA-transfected target cells than did +/+ control mice. Thus, CD7-deficient mice did not have a SCID syndrome, but rather had transient increases in thymocyte numbers at age 3 mo and altered splenocyte Ag-specific CTL effecter cell activity. These data suggest a role for CD7 in regulating intrathymic T cell development and in mediating CTL effecter function.


Chemical agents and peptides affect hair growth.
During the past decade we have examined both the therapeutic and the prophylactic effects of several agents on the macaque model of androgenetic alopecia. Minoxidil and diazoxide, potent hypotensive agents acting as peripheral vasodilators, are known to have a hypertrichotic side effect. Topical use of both agents induced significant hair regrowth in the bald scalps of macaques. The application of a steroid 5 alpha-reductase inhibitor (4MA) in non-bald preadolescent macaques has prevented baldness, whereas controls developed it during 2 years of treatment. The effects of hair growth were determined by 1) phototrichogram, 2) folliculogram (micro-morphometric analysis), and 3) the rate of DNA synthesis in the follicular cells. These effects were essentially a stimulation of the follicular cell proliferation, resulting in an enlargement of the anagen follicles from vellus to terminal type (therapy) or a maintenance of the prebald terminal follicles (prevention). A copper binding peptide (PC1031) had the effect of follicular enlargement on the back skin of fuzzy rats, covering the vellus follicles; the effect was similar to that of topical minoxidil. Analyzing the quantitative sequences of follicular size and cyclic phases, we speculate on the effect of agents on follicular growth. We also discuss the triggering mechanism of androgen in the follicular epithelial-mesenchymal (dermal papilla) interaction.


K+ and Rb+ transport by the rabbit CCD: Rb+ reduces K+ conductance and Na+ transport.
We compared transport of K+ and Rb+ across the rabbit cortical collecting duct to gain insight into the mechanisms of K+ secretion. Passive tracer fluxes, active secretory rates, electrophysiological behavior, and the ability of each ion to support Na+-K+-ATPase activity were determined. When active transport was inhibited by amiloride, K+ permeability was twice the Rb+ permeability. Transepithelial conductance (GT) was half as great in solutions where 5 mM Rb+ replaced 5 mM K+. When 4 mM Ba2+ was added to the lumen, both Rb+ and K+ permeability fell to values not different from that expected for paracellular diffusion. The relationship between Ba2+-induced changes in the K+ and Rb+ permeabilities and in the simultaneously measured GT provides strong evidence that K+ transport across the apical membrane is largely, if not exclusively, conductive. We also determined that net K+ secretion is greater than net Rb+ secretion (when each is the abundant ion). The reasons for this difference probably involve several steps in the K+ secretory process and include the following: 1) reduced ATPase activity in the presence of Rb+ (approximately 80%) compared with K+, 2) reduction of Na+ absorption, and 3) partial blockade of the apical (and perhaps basolateral) K+ conductance. Although there were quantitative differences between K+ and Rb+ transport, we found no evidence suggesting that these ions are transported by different mechanisms.


Evaluation of a PCR melting profile method for intraspecies differentiation of Trichophyton rubrum and Trichophyton interdigitale.
In order to identify the source of infections caused by dermatophytes, as well as the pathogen transmission pathway, there is a need to determine methods that allow detailed genetic differentiation of the strains within the dermatophyte genera. In this work, a PCR melting profile (PCR-MP) technique based on the ligation of adaptors and the difference in melting temperatures of DNA restriction fragments was used for the first time for intraspecies genotyping of dermatophytes. Clinical isolates and reference strains of dermatophytes isolated from skin, scalp, toenails and fingernails were used for this study. PCR-MP and random amplification of polymorphic DNA (RAPD) were used to type 11 isolates of Trichophyton rubrum, 40 isolates of Trichophyton interdigitale and 14 isolates of Microsporum canis. The results distinguished five types (containing one subtype) characteristic for T. rubrum and seven types characteristic for T. interdigitale using the PCR-MP technique. Analysis conducted using RAPD revealed five types for T. rubrum and four types for T. interdigitale isolates. No differentiation was observed for the M. canis isolates with either method. These results demonstrate that PCR-MP is a reliable method for the differentiation of T. rubrum and T. interdigitale strains and yields a discriminatory power that is at least equal to that of RAPD.


Autocrine VEGF signaling promotes proliferation of neoplastic Barrett's epithelial cells through a PLC-dependent pathway.
Tumor cells express vascular endothelial growth factor (VEGF), which induces angiogenesis. VEGF also activates VEGF receptors (VEGFRs) on or within tumor cells to promote their proliferation in an autocrine fashion. We studied the mechanisms of autocrine VEGF signaling in Barrett's esophagus cells. Using Barrett's epithelial cell lines, we measured VEGF and VEGFR messenger RNA and protein, and studied the effects of VEGF signaling on cell proliferation and VEGF secretion. We studied the effects of inhibiting factors in this pathway on levels of phosphorylated phospholipase Cγ1 (PLCG1), protein kinase C, and extracellular signal-regulated kinases (ERK)1/2. We performed immunohistochemical analysis of phosphorylated VEGFR2 on esophageal adenocarcinoma tissues. We studied effects of sunitinib, a VEGFR2 inhibitor, on proliferation of neoplastic cells and growth of xenograft tumors in mice. Neoplastic and non-neoplastic Barrett's cells expressed VEGF and VEGFR2 messenger RNA and protein, with higher levels in neoplastic cells. Incubation with recombinant human VEGF significantly increased secretion of VEGF protein and cell number; knockdown of PLCG1 markedly reduced the recombinant human VEGF-stimulated increase in levels of phosphorylated PLCG1 and phosphorylated ERK1/2 in neoplastic cells. Esophageal adenocarcinoma tissues showed immunostaining for phosphorylated VEGFR2. Sunitinib inhibited VEGF signaling in neoplastic cells and reduced weight and volume of xenograft tumors in mice. Neoplastic and non-neoplastic Barrett's epithelial cells have autocrine VEGF signaling. In neoplastic Barrett's cells, VEGF activation of VEGFR2 initiates a PLCG1-protein kinase C-ERK pathway that promotes proliferation and is self-sustaining (by causing more VEGF production). Strategies to reduce autocrine VEGF signaling (eg, with sunitinib) might be used to prevent or treat cancer in patients with Barrett's esophagus.


Incidence of HIV in Windhoek, Namibia: demographic and socio-economic associations.
To estimate HIV incidence and prevalence in Windhoek, Namibia and to analyze socio-economic factors related to HIV infection. In 2006/7, baseline surveys were performed with 1,753 private households living in the greater Windhoek area; follow-up visits took place in 2008 and 2009. Face-to-face socio-economic questionnaires were administrated by trained interviewers; biomedical markers were collected by nurses; GPS codes of household residences were recorded. The HIV prevalence in the population (aged>12 years) was 11.8% in 2006/7 and 14.6% in 2009. HIV incidence between 2007 and 2009 was 2.4 per 100 person year (95%CI = 1.9-2.9). HIV incidence and prevalence were higher in female populations. HIV incidence appeared non-associated with any socioeconomic factor, indicating universal risk for the population. For women a positive trend was found between low per-capita consumption and HIV acquisition. A HIV knowledge score was strongly associated with HIV incidence for both men and women. High HIV prevalence and incidence was concentrated in the north-western part of the city, an area with lower HIV knowledge, higher HIV risk perception and lower per-capita consumption. The HIV incidence and prevalence figures do not suggest a declining epidemic in Windhoek. Higher vulnerability of women is recorded, most likely related to economic dependency and increasing transactional sex in Namibia. The lack of relation between HIV incidence and socio-economic factors confirms HIV risks for the overall urban community. Appropriate knowledge is strongly associated to lower HIV incidence and prevalence, underscoring the importance of continuous information and education activities for prevention of infection. Geographical areas were identified that would require prioritized HIV campaigning.


Structural requirements for pairing of alpha and beta chains in HLA-DR and HLA-DP molecules.
To test for the assembly of human MHC class II molecules having an alpha chain from one isotype (HLA-DR, -DQ, or -DP) and the beta chain of another (mixed isotypic pairs), murine fibroblasts were transfected with expressible cDNAs encoding the different class II alpha and beta chains. A rapid and efficient transient transfection system was developed using a polyoma virus-based vector. Typically, 30-50% of cells transfected using this system expressed high levels of class II molecules on their surface, but only with matched isotypic pairs. Biochemical analysis of cells transfected with matched or mixed isotypic pairs of the DR and DP molecules revealed that only matched chains could pair efficiently inside the cell. Thus, the lack of expression of the two mixed isotypic pairs is due to inefficient primary assembly of the class II molecule and not to a processing or transport defect. To define what region of the beta chains controlled their assembly with alpha chains, a series of chimeric cDNA molecules containing both DR and DP beta chain sequences were constructed. Expression of these chimeric beta chains with DR and DP alpha chains was determined by cytofluorimetry and biochemical analysis. Both alpha chains paired with beta chains in which only the beta 1 domain was isotypically matched. In contrast, the pattern of expression of chimeras made at other points within the beta 1 domain was different for DR and DP. These data show that different areas of primary sequence are important for the assembly of different human class II isotypes, and suggest that HLA-DR and -DP molecules have different secondary or tertiary structures in their NH2-terminal domains.


Serotonin receptor 1A knockout: an animal model of anxiety-related disorder.
To investigate the contribution of individual serotonin (5-hydroxytryptamine; 5-HT) receptors to mood control, we have used homologous recombination to generate mice lacking specific serotonergic receptor subtypes. In the present report, we demonstrate that mice without 5-HT1A receptors display decreased exploratory activity and increased fear of aversive environments (open or elevated spaces). 5-HT1A knockout mice also exhibited a decreased immobility in the forced swim test, an effect commonly associated with antidepressant treatment. Although 5-HT1A receptors are involved in controlling the activity of serotonergic neurons, 5-HT1A knockout mice had normal levels of 5-HT and 5-hydroxyindoleacetic acid, possibly because of an up-regulation of 5-HT1B autoreceptors. Heterozygote 5-HT1A mutants expressed approximately one-half of wild-type receptor density and displayed intermediate phenotypes in most behavioral tests. These results demonstrate that 5-HT1A receptors are involved in the modulation of exploratory and fear-related behaviors and suggest that reductions in 5-HT1A receptor density due to genetic defects or environmental stressors might result in heightened anxiety.


Differentiation of prostatitis and prostate cancer by using diffusion-weighted MR imaging and MR-guided biopsy at 3 T.
To determine if prostatitis and prostate cancer (PCa) can be distinguished by using apparent diffusion coefficients (ADCs) on magnetic resonance (MR) images, with specimens obtained at MR-guided biopsy as the standard of reference. The need for institutional review board approval and informed consent was waived. MR-guided biopsies were performed in 130 consecutive patients with cancer-suspicious regions (CSRs) on multiparametric MR images obtained at 3 T. In this retrospective study, 88 patients met the inclusion criteria. During the biopsy procedure, an axial diffusion-weighted sequence was performed and ADC maps were generated (repetition time msec/echo time msec, 2000/67; section thickness, 4 mm; in-plane resolution, 1.8 × 1.8 mm; and b values of 0, 100, 500, and 800 sec/mm(2)). Subsequently, a confirmation image with the needle left in situ was acquired and projected on the ADC map. The corresponding ADCs at the biopsy location were compared with the histopathologic outcomes of the biopsy specimens. Linear mixed-model regression analyses were used to test for ADC differences between the histopathologic groups. The study included 116 biopsy specimens. Median ADCs of normal prostate tissue, prostatitis, low-grade PCa (Gleason grade components 2 or 3), and high-grade PCa (Gleason grade components 4 or 5) were 1.22 × 10(-3) mm(2)/sec (standard deviation, ± 0.21), 1.08 × 10(-3) mm(2)/sec (± 0.18), 0.88 × 10(-3) mm(2)/sec (± 0.15), and 0.88 × 10(-3) mm(2)/sec (± 0.13), respectively. Although the median ADCs of biopsy specimens with prostatitis were significantly higher compared with low- and high-grade PCa (P < .001), there is a considerable overlap between the tissue types. Diffusion-weighted imaging is a noninvasive technique that shows differences between prostatitis and PCa in both the peripheral zone and central gland, although its usability in clinical practice is limited as a result of significant overlap in ADCs.


High efficiency laser action of 1% at. Yb3+:2O3 ceramic.
We report the spectroscopic characteristics and the laser performances of a low-doped 1% at. Yb:Sc(2)O(3) ceramic sample. Under end- pumping at 933 nm and 968 nm in quasi-CW mode, at 1040.5 nm the laser delivers a maximum output power of 4.3 W and 1.77 W, respectively with a corresponding slope efficiency of 74% and 80%, which are, to the best of our knowledge, the highest value reported in literature for ceramics. We explored the tuning range of the sample, which spans from 1005 nm to 1050.5 nm, and finally we characterized the low losses tunable cavity at 1032 nm.


Decadal declines in avian herbivore reproduction: density-dependent nutrition and phenological mismatch in the Arctic.
A full understanding of population dynamics depends not only on estimation of mechanistic contributions of recruitment and survival, but also knowledge about the ecological processes that drive each of these vital rates. The process of recruitment in particular may be protracted over several years, and can depend on numerous ecological complexities until sexually mature adulthood is attained. We addressed long-term declines (23 breeding seasons, 1992-2014) in the per capita production of young by both Ross's Geese (Chen rossii) and Lesser Snow Geese (Chen caerulescens caerulescens) nesting at Karrak Lake in Canada's central Arctic. During this period, there was a contemporaneous increase from 0.4 to 1.1 million adults nesting at this colony. We evaluated whether (1) density-dependent nutritional deficiencies of pre-breeding females or (2) phenological mismatch between peak gosling hatch and peak forage quality, inferred from NDVI on the brood-rearing areas, may have been behind decadal declines in the per capita production of goslings. We found that, in years when pre-breeding females arrived to the nesting grounds with diminished nutrient reserves, the proportional composition of young during brood-rearing was reduced for both species. Furthermore, increased mismatch between peak gosling hatch and peak forage quality contributed additively to further declines in gosling production, in addition to declines caused by delayed nesting with associated subsequent negative effects on clutch size and nest success. The degree of mismatch increased over the course of our study because of advanced vegetation phenology without a corresponding advance in Goose nesting phenology. Vegetation phenology was significantly earlier in years with warm surface air temperatures measured in spring (i.e., 25 May-30 June). We suggest that both increased phenological mismatch and reduced nutritional condition of arriving females were behind declines in population-level recruitment, leading to the recent attenuation in population growth of Snow Geese.


The impact of single-dose diethylcarbamazine treatment of bancroftian filariasis in a low-endemicity setting in Egypt.
This study was designed to evaluate the effect of a single dose of diethylcarbamazine (DEC, 6 mg/kg) on Wuchereria bancrofti infections in a low-endemicity setting in Egypt (microfilaremia, or MF, 3.7%, median MF 34/mL). Subjects with MF or filarial antigenemia were treated and restudied 1 year later. Treatment with DEC dramatically reduced blood MF counts, with clearance in 69% of subjects. Treatment also reduced filarial antigen levels, but low clearance rates suggest that some adult worms survived treatment in most patients. Mass treatment was administered in one village; 27 months later, MF prevalence had decreased 84% (from 4.9% to 0.8%). These results show that single-dose DEC treatment can have a major effect on MF prevalence rates and levels in low-endemicity settings. Although the World Health Organization advocates repeated multidrug regimens for filariasis elimination, mass treatment with DEC alone may be sufficient to interrupt transmission in areas with low infection intensities and prevalence rates.


Immunofibrogenic Gene Expression Patterns in Tanzanian Children with Ocular Chlamydia trachomatis Infection, Active Trachoma and Scarring: Baseline Results of a 4-Year Longitudinal Study.
Trachoma, caused by Chlamydia trachomatis, is the world's leading infectious cause of blindness and remains a significant public health problem. Much of trachomatous disease pathology is thought to be caused indirectly by host cellular and immune responses, however the immune response during active trachoma and how this initiates progressive scarring is not clearly understood. Defining protective vs. pathogenic immune response to C. trachomatis is important for vaccine design and evaluation. This study reports the baseline results of a longitudinal cohort of Tanzanian children, who were monitored for 4 years in order to determine the immunofibrogenic and infectious correlates of progressive scarring trachoma. In this cohort baseline, 506 children aged 6-10 years were assessed for clinical signs, infection status and the expression of 91 genes of interest prior to mass azithromycin administration for trachoma control. C. trachomatis was detected using droplet digital PCR and gene expression was measured using quantitative real-time PCR. The prevalence of follicles, papillary inflammation and scarring were 33.6, 31.6, and 28.5%, respectively. C. trachomatis was detected in 78/506 (15.4%) individuals, 62/78 of whom also had follicles. C. trachomatis infection was associated with a strong upregulation of IFNG and IL22, the enrichment of Th1 and NK cell pathways and Th17 cell-associated cytokines. In individuals with inflammation in the absence of infection the IFNG/IL22 and NK cell response was reduced, however, pro-inflammatory, growth and matrix factors remained upregulated and mucins were downregulated. Our data suggest that, strong IFNG/IL22 responses, probably related to Th1 and NK cell involvement, is important for clearance of C. trachomatis and that the residual pro-inflammatory and pro-fibrotic phenotype that persists after infection might contribute to pathological scarring. Interestingly, females appear more susceptible to developing papillary inflammation and scarring than males, even at this young age, despite comparable levels of C. trachomatis infection. Females also had increased expression of a number of IFNγ pathway related genes relative to males, suggesting that overexpression of this pathway in response to infection might contribute to more severe scarring. Longitudinal investigation of these factors will reveal their relative contributions to protection from C. trachomatis infection and development of scarring complications.


The role of clonal selection in the pathogenesis of an autoreactive human B cell lymphoma.
To study the association of autoimmunity and human B cell neoplasia, we have established a model of a B cell lymphoma which expresses a pathogenic autoantibody of defined specificity. The Ig VH gene expressed in this neoplasm was analyzed longitudinally using clinical specimens taken from the splenic lymphoma (S) at diagnosis and from lymph node relapses 3 and 4 yr later (N3 and N4). Southern analysis and oligonucleotide hybridization experiments demonstrated that clonally related predominant and minor tumor cell populations were present in S at diagnosis, and that the minor population became the predominant population in the relapse specimens, N3 and N4. Although the Ig specificity and idiotype were the same at diagnosis and at both relapses, analysis of the expressed VH gene sequences showed 14 base changes between S and N3, and 2 further changes at N4. Little sequence heterogeneity was observed at each sampling time, indicating that the ongoing mutation frequency was low. The relevant germline precursor VH gene was determined from autologous germline DNA and compared to the expressed genes. Based on the pattern of shared and unshared mutations, we were able to establish the genealogic relationship of the germline VH gene and the expressed clonotypes of S, N3 and N4. Taken together, the findings from Southern blotting, oligonucleotide hybridization, and sequence analysis permit us to describe a molecular aspect of tumor progression, "clonotypic shift", wherein subpopulations of the malignant clone, marked by different V gene clonotypes, emerge and predominate at different time points in the evolution of the lymphoma. Furthermore, the sequential and nonrandom pattern of the VH mutations, correlated with the observed conservation of autospecificity and idiotype, implies that clonal selection may have influenced the pathogenesis of the lymphoma.


Living with diabetes: rationale, study design and baseline characteristics for an Australian prospective cohort study.
Diabetes mellitus is a major global public health threat. In Australia, as elsewhere, it is responsible for a sizeable portion of the overall burden of disease, and significant costs. The psychological and social impact of diabetes on individuals with the disease can be severe, and if not adequately addressed, can lead to the worsening of the overall disease picture. The Living With Diabetes Study aims to contribute to a holistic understanding of the psychological and social aspects of diabetes mellitus. The Living With Diabetes Study is a 5-year prospective cohort study, based in Queensland, Australia. The first wave of data, which was collected via a mailed self-report survey, was gathered in 2008, with annual collections thereafter. Measurements include: demographic, lifestyle, health and disease characteristics; quality of life (EQ-5D, ADDQoL); emotional well-being (CES-D, LOT-R, ESSI); disease self-management (PAM); and health-care utilisation and patient-assessed quality of care (PACIC). 29% of the 14,439 adults who were invited to participate in the study agreed to do so, yielding a sample size of 3,951 people. The data collected by the Living With Diabetes Study provides a good representation of Australians with diabetes to follow over time in order to better understand the natural course of the illness. The study has potential to further illuminate, and give a comprehensive picture of the psychosocial implications of living with diabetes. Data collection is ongoing.


Blood-based biomarkers for malignant gliomas.
Malignant gliomas remain incurable and present unique challenges to clinicians, radiologists and clinical and translational investigators. One of the major problems in treatment of these tumors is our limited ability to reliably assess tumor response or progression. The most frequently used neuro-imaging studies (contrast-enhanced MRI and CT) rely on changes of blood-brain barrier (BBB) integrity, providing only an indirect assessment of tumor burden. In addition, the BBB can be altered by commonly used interventions including radiation, glucocorticoids and vascular endothelial growth factor inhibitors, further complicating the interpretation of scans. Newer radiologic techniques including PET and magnetic resonance spectroscopy are theoretically promising but thus far have not meaningfully changed the assessment of patients with malignant gliomas. A tumor-specific, blood-based biomarker would be of immediate use to clinicians and investigators if sufficiently sensitive and specific. This review discusses the potential utility of such a biomarker, the general classes of tumor-derived blood-based biomarkers and it summarizes the currently available data on circulating tumor cells, circulating nucleic acids and circulating proteins in patients with malignant gliomas. It is unclear which marker or marker class appears to be the most promising for these tumors. This article provides thoughts on how novel candidate blood-based markers could be discovered and tested in a more comprehensive way and why these efforts should be among the top priorities in neuro-oncologic research in the coming years.


Development of interactive empowerment services in support of personalised medicine.
In an epoch where shared decision making is gaining importance, a patient's commitment to and knowledge about his/her health condition is becoming more and more relevant. Health literacy is one of the most important factors in enhancing the involvement of patients in their care. Nevertheless, other factors can impair patient processing and understanding of health information: psychological aspects and cognitive style may affect the way patients approach, select, and retain information. This paper describes the development and validation of a short and easy to fill-out questionnaire that measures and collects psycho-cognitive information about patients, named ALGA-C. ALGA-C is a multilingual, multidevice instrument, and its validation was carried out in healthy people and breast cancer patients. In addition to the aforementioned questionnaire, a patient profiling mechanism has also been developed. The ALGA-C Profiler enables physicians to rapidly inspect each patient's individual cognitive profile and see at a glance the areas of concern. With this tool, doctors can modulate the language, vocabulary, and content of subsequent discussions with the patient, thus enabling easier understanding by the patient. This, in turn, helps the patient formulate questions and participate on an equal footing in the decision-making processes. Finally, a preview is given on the techniques under consideration for exploiting the constructed patient profile by a personal health record (PHR). Predefined rules will use a patient's profile to personalise the contents of the information presented and to customise ways in which users complete their tasks in a PHR system. This optimises information delivery to patients and makes it easier for the patient to decide what is of interest to him/her at the moment.


Human bronchial epithelial and endothelial cells express alpha7 nicotinic acetylcholine receptors.
The epithelial or endothelial cells that line the human bronchi and the aorta express nicotinic acetylcholine receptors (nAChRs) of alpha3 subtypes. We report here that human bronchial epithelial cells (BEC) and aortic endothelial cells (AEC) express also the nAChR alpha7 subunit, which forms functional nAChRs. Polymerase chain reaction and in situ hybridization experiments detected alpha7 subunit mRNA in cultured human BEC and AEC and in sections of rat trachea. The binding of radiolabeled alpha-bungarotoxin revealed a few thousand binding sites per cell in cultured human BEC and human and bovine AEC. Western blot and immunohistochemistry experiments demonstrated that cultured BEC and AEC express a protein(s) recognized by anti-alpha7 antibodies. Whole-cell patch-clamp studies of cultured human BEC demonstrated the presence of fast-desensitizing currents activated by choline and nicotine that were blocked reversibly by methyllycaconitine (1 nM) and irreversibly by alpha-bungarotoxin (100 nM), consistent with the expression of functional alpha7 nAChRs. In some cells, choline activated also slowly decaying currents, confirming previous reports that BEC express functional alpha3beta4 nAChRs. Exposure of cultured BEC to nicotine (1 microM) for 3 days up-regulated functional alpha7 and alpha3 nAChRs, as indicated by the increased number of cells responding to acetylcholine and choline, with both fast-desensitizing currents, which were blocked irreversibly by alpha-bungarotoxin, and with slowly desensitizing currents, which are alpha-bungarotoxin-insensitive currents. The presence of alpha7 nAChRs in BEC and AEC suggests that some toxic effects of tobacco smoke could be mediated through these nicotine-sensitive receptors.


Barriers built on claudins.
The fundamental functions of epithelia and endothelia in multicellular organisms are to separate compositionally distinct compartments and regulate the exchange of small solutes and other substances between them. Tight junctions (TJs) between adjacent cells constitute the barrier to the passage of ions and molecules through the paracellular pathway and function as a 'fence' within the plasma membrane to create and maintain apical and basolateral membrane domains. How TJs achieve this is only beginning to be understood. Recently identified components of TJs include the claudins, a family of four-transmembrane-span proteins that are prime candidates for molecules that function in TJ permeability. Their identification and characterization have provided new insight into the diversity of different TJs and heterogeneity of barrier functions in different epithelia and endothelia.


Spiritist psychiatric hospitals in Brazil: integration of conventional psychiatric treatment and spiritual complementary therapy.
In Brazil, during the XX century, dozens of Spiritist psychiatric hospitals emerged seeking to integrate conventional medical treatment with complementary spiritual therapy. This combined inpatient treatment is largely found in Brazil, where many psychiatric hospitals stem from the Spiritist movement. The present report describes the use of these spiritual practices, their operating structure, health professionals involved, modalities of care, and institutional difficulties in integrating spiritual practices with conventional treatment in six leading Brazilian Spiritist psychiatric hospitals. These hospitals combine conventional psychiatric treatment with voluntary-based spiritual approaches such as laying on of hands ("fluidotherapy"), lectures regarding spiritual and ethical issues, intercessory prayer, spirit release therapy ("disobsession") and "fraternal dialogue". The non-indoctrination and optional nature of these spiritual complementary therapies seem to increase acceptance among patients and their family members. In conclusion, the Spiritist psychiatric hospitals in Brazil have, for more than half a century, provided an integrative approach in the treatment of psychiatric disorders, associating conventional and spiritual treatments, more specifically Spiritist therapy. The lack of standardized treatment protocols and scientific studies remain a barrier to assessing the impact of this integrative approach on patients' mental health, quality of life, adherence, and perceived quality of treatment.


Recent advances in transition-metal dichalcogenide based nanomaterials for water splitting.
The desire for sustainable and clean energy future continues to be the concern of the scientific community. Researchers are incessantly targeting the development of scalable and abundant electro- or photo-catalysts for water splitting. Owing to their suitable band-gap and excellent stability, an enormous amount of transition-metal dichalcogenides (TMDs) with hierarchical nanostructures have been extensively explored. Herein, we present an overview of the recent research progresses in the design, characterization and applications of the TMD-based electro- or photo-catalysts for hydrogen and oxygen evolution. Emphasis is given to the layered and pyrite-phase structured TMDs encompassing semiconducting and metallic nanomaterials. Illustrative results and the future prospects are pointed out. This review will provide the readers with insight into the state-of-the-art research progresses in TMD based nanomaterials for water splitting.


Field diversity phase retrieval method for wavefront sensing in monolithic mirror space telescopes.
To guarantee the uniqueness of the solution for the wavefront phase, a series of intensity images with known phase diversities is usually needed in the current phase retrieval wavefront sensing methods. However, to obtain these intensity images with deliberately added diversity phases, some additional instruments (e.g., beam splitters) or operations (e.g., adjustment of the focus) are usually needed, which can pose a challenge for wavefront sensing in space telescopes. This paper proposes a new concept for retrieving the wavefront phase of monolithic mirror space telescopes with perturbations, where the intensity measurements with phase diversities are directly obtained from different field positions of one image, without the need for any additional instruments or operations. To realize this new concept, we present a modified phase diversity method to account for the unknown phase diversities between these intensity measurements based on an in-depth understanding of the net aberration fields induced by misalignments and figure errors. Relevant simulations for different cases are performed to demonstrate the feasibility and accuracy of the proposed method. Since in this method the phase diversities between different intensity measurements are mainly induced by the diversities in the field position, we call it the field diversity phase retrieval method. This work can present great facility for wavefront sensing in monolithic mirror space telescopes.


Child- and Parent-Related Correlates of Total and Prolonged Sedentary Time in 5- to 6-Year-Old Children.
The primary aim was to examine child- and parent-related correlates of accelerometer-assessed overall total and prolonged (i.e., accumulated in bouts of ≥10 consecutive minutes) sedentary time (SED) in 5- to 6-year-old children. Second, child- and parent-related correlates of total and prolonged SED during weekend days and the after school period were examined, as associations with parent-related correlates may be stronger during these periods. SED and moderate-to-vigorous-intensity physical activity (MVPA) were assessed by ActiGraph accelerometers in children (n = 836) and one of their parents/carers. Parents completed a questionnaire examining potential parent-related correlates. Multilevel models examined associations between potential correlates and children's total and prolonged SED. Children's MVPA was the only correlate that was consistently negatively associated with both total and prolonged SED across the different time periods (overall, after school, and weekend days). Higher total SED in parents was associated with higher overall total SED and weekend total SED in children. Higher body mass index z-scores of children were associated with lower overall total and prolonged SED. Girls had lower prolonged SED after school than boys. Older children had lower total SED during the weekend. In conclusion, few potential correlates were associated with young children's total or prolonged SED and most associations differed by time period.


RBP-L, a transcription factor related to RBP-Jkappa.
RBP-Jkappa is a sequence-specific DNA binding protein which plays a central role in signalling downstream of the Notch receptor by physically interacting with its intracellular region. Although at least four Notch genes exist in mammals, it is unknown whether each Notch requires a specific downstream signalling molecule. Here we report isolation and characterization of a mouse RBP-Jkappa-related gene named RBP-L that is expressed almost exclusively in lung, in contrast to the ubiquitous expression of RBP-Jkappa. For simplicity, we propose to call RBP-Jkappa RBP-J. The RBP-L protein bound to a DNA sequence almost identical to that of RBP-J. Surprisingly, RBP-L did not interact with any of the known four mouse Notch proteins. Although we found that RBP-L and EBNA-2 cooperated in transcriptional activation, they did not show significantly strong protein-protein interaction that can be detected by several in vivo and in vitro assays. This is again in contrast to physical association of RBP-J with EBNA-2. Several models to explain functional interaction between RBP-L and EBNA-2 are discussed.


The emerging evidence for long-term psychodynamic therapy.
There is growing evidence from RCTs supporting the efficacy of both short-term (STPP) and long-term psychodynamic psychotherapy (LTPP) for specific mental disorders. In a first series of meta-analyses, LTPP was shown to be superior to shorter forms of psychotherapy, especially in complex mental disorders. However, the evidence for LTPP has not gone unchallenged. After several responses have addressed the raised concerns, a recent meta-analysis by Smit and colleagues (2012) again challenges the efficacy of LTPP. From a methodological perspective, a critical analysis of the Smit et al. meta-analysis was performed. Furthermore, we conducted two new metaanalyses adding studies not included in previous meta-analyses. The purpose was to examine whether the results of the previous meta-analyses are stable. Due to differing inclusion criteria, the meta-analysis by Smit et al. actually compared LTPP to other forms of long-term psychotherapy. Thus, they essentially showed that LTPP was as efficacious as other forms of long-term therapy. For this reason the meta-analysis by Smit et al. does not question the results of previous meta-analyses showing that LTPP is superior to shorter forms of psychotherapy. In addition, the Smit et al. meta-analysis was shown to suffer from several methodological shortcomings. The new meta-analyses we performed did not find significant deviations from previous results. In complex mental disorders LTPP proved to be significantly superior to shorter forms of therapy corroborating results of previous meta-analyses. Data on dose-effect relations suggest that for many patients with complex mental disorders, including chronic mental disorders and personality disorders, short-term psychotherapy is not sufficient. For these patients, long-term treatments may be indicated. The meta-analyses presented here provide further support for LTPP in these populations. Nevertheless, there is a need for more research in LTPP and other long-term psychotherapies.


Uncovering cryptic diversity and refugial persistence among small mammal lineages across the Eastern Afromontane biodiversity hotspot.
The Eastern Afromontane region of Africa is characterized by striking levels of endemism and species richness accompanied by significant conservation threat, a pattern typical across biodiversity hotspots. Using multi-locus molecular data under a coalescent species tree framework we identify major cryptic biogeographic patterns within and between two endemic montane small mammal species complexes, Hylomyscus mice and Sylvisorex shrews, co-distributed across the Albertine Rift and Kenya Highlands of the Eastern Afromontane Biodiversity Hotspot (EABH). Hypotheses put forward to account for the high diversity of the region include retention of older palaeo-endemic lineages across major regions in climatically stable refugia, as well as the accumulation of lineages associated with more recent differentiation between allopatric populations separated by unsuitable habitat during periods of Pleistocene aridification. Sympatric pairs of sister lineages were found to have significantly older divergence times than allopatric pairs. Genetic analyses and historical distribution modeling suggest that regional meta-populations have persisted since the Pliocene to mid-Pleistocene across a climatic gradient from the Albertine Rift in the west to the Kenya Highlands in the east for both focal taxa. Differing patterns of regional sub-division and demographic expansion were detected and are consistent with differing life histories as well as shared responses to regional variation in stability of suitable habitat. There is also strong support in both mice and shrew species for Late Miocene divergence with subsequent range expansion into sympatry in previously unidentified cryptic species pairs. These results highlight the broad temporal scale at which climatic and geological changes may have facilitated rare dispersal events between montane habitats as well as the long-term persistence of populations in both the Albertine Rift and the Kenyan Highlands that together contributed to the high species diversity and endemism in the EABH.


Born to learn: The inspiration, progress, and future of evolved plastic artificial neural networks.
Biological neural networks are systems of extraordinary computational capabilities shaped by evolution, development, and lifelong learning. The interplay of these elements leads to the emergence of biological intelligence. Inspired by such intricate natural phenomena, Evolved Plastic Artificial Neural Networks (EPANNs) employ simulated evolution in-silico to breed plastic neural networks with the aim to autonomously design and create learning systems. EPANN experiments evolve networks that include both innate properties and the ability to change and learn in response to experiences in different environments and problem domains. EPANNs' aims include autonomously creating learning systems, bootstrapping learning from scratch, recovering performance in unseen conditions, testing the computational advantages of particular neural components, and deriving hypotheses on the emergence of biological learning. Thus, EPANNs may include a large variety of different neuron types and dynamics, network architectures, plasticity rules, and other factors. While EPANNs have seen considerable progress over the last two decades, current scientific and technological advances in artificial neural networks are setting the conditions for radically new approaches and results. Exploiting the increased availability of computational resources and of simulation environments, the often challenging task of hand-designing learning neural networks could be replaced by more autonomous and creative processes. This paper brings together a variety of inspiring ideas that define the field of EPANNs. The main methods and results are reviewed. Finally, new opportunities and possible developments are presented.


Interassociation consensus statement on cardiovascular care of college student-athletes.
Cardiovascular evaluation and care of college student-athletes is gaining increasing attention from both the public and medical communities. Emerging strategies include screening of the general athlete population, recommendations of permissible levels of participation by athletes with identified cardiovascular conditions and preparation for responding to unanticipated cardiac events in athletic venues. The primary focus has been sudden cardiac death and the usefulness of screening with or without advanced cardiac screening. The National Collegiate Athletic Association convened a multidisciplinary task force to address cardiovascular concerns in collegiate student-athletes, and to develop consensus for an interassociation statement. This document summarises the task force deliberations and follow-up discussions, and includes available evidence on cardiovascular risk, preparticipation evaluation and the recognition of and response to cardiac arrest. Future recommendations for cardiac research initiatives, education and collaboration are also provided.