Dynamics of memory-guided choice behavior in Drosophila.
Memory retrieval requires both accuracy and speed. Olfactory learning of the fruit fly Drosophila melanogaster serves as a powerful model system to identify molecular and neuronal substrates of memory and memory-guided behavior. The behavioral expression of olfactory memory has traditionally been tested as a conditioned odor response in a simple T-maze, which measures the result, but not the speed, of odor choice. Here, we developed multiplexed T-mazes that allow video recording of the choice behavior. Automatic fly counting in each arm of the maze visualizes choice dynamics. Using this setup, we show that the transient blockade of serotonergic neurons slows down the choice, while leaving the eventual choice intact. In contrast, activation of the same neurons impairs the eventual performance leaving the choice speed unchanged. Our new apparatus contributes to elucidating how the speed and the accuracy of memory retrieval are implemented in the fly brain.


Sustainability of locally driven centres for those affected by dementia: a protocol for the get real with meeting centres realist evaluation.
Improving support for people with early to moderate dementia to live at home in their communities is a global public health goal. Community adult social care is not robust in many parts of the UK, however, with the pandemic increasing pressure on services for this population. Community-led interventions can play a key role in supporting people postdiagnosis, helping delay decline, but many interventions struggle to sustain beyond 1-2 years. Meeting Centres (MCs) are one such intervention, which many UK community groups find attractive and achievable. However, it is not understood how these communities can ensure they are putting in place strategies that will help them sustain in the longer term, beyond start-up phase. This realist evaluation aims to understand the factors affecting sustainability of MCs in rural areas and learn lessons from MCs that have sustained beyond 3 years. Data will be collected using mixed methods: interviews and group discussions with stakeholders involved at every level in three case study locations in England and Wales, analysed with Soft Systems modelling; a Discrete Choice Experiment exploring what people across the UK value and are willing to pay for MCs, analysed with regression modelling. All data will be synthesised using a Realist logic of analysis to build a theoretical model of how, why, for whom, in what contexts and to what extent MCs can be successfully implemented for the long term. As participants may lack capacity for informed consent, favourable ethical opinion was received from a Health Research Authority research ethics committee. Resulting recommendations will be of interest to stakeholders including those commissioning, planning, running, supporting or attending MCs, as well as policy-makers and healthcare professionals. Knowledge will be shared with emerging MCs to help accelerate scale up of this intervention.


2,6-Diiminopiperidin-1-ol: an overlooked motif relevant to uranyl and transition metal binding on poly(amidoxime) adsorbents.
Glutardiamidoxime, a structural motif on sorbents used in uranium extraction from seawater, was discovered to cyclize in situ at room temperature to 2,6-diimino-piperidin-1-ol in the presence of uranyl nitrate. The new diimino motif was also generated when exposed to competing transition metals Cu(ii) and Ni(ii). Multinuclear μ-O bridged U(vi), Cu(ii), and Ni(ii) complexes featuring bound diimino ligands were isolated.


Cognitive Factories: Modeling Situated Entropy in Physical Work Carried Out by Humans and Robots.
Entropy in factories is situated. For example, there can be numerous different ways of picking, orientating, and placing physical components during assembly work. Physical components can be redesigned to increase the Information Gain they provide and so reduce situated entropy in assembly work. Also, situated entropy is affected by the extent of knowledge of those doing the work. For example, work can be done by knowledgeable experts or by beginners who lack knowledge about physical components, etc. The number of different ways that work can be done and the knowledge of the worker combine to affect cognitive load. Thus, situated entropy in factories relates to situated cognition within which knowledge is bound to physical contexts and knowing is inseparable from doing. In this paper, six contributions are provided for modelling situated entropy in factories. First, theoretical frameworks are brought together to provide a conceptual framework for modelling. Second, the conceptual framework is related to physical production using practical examples. Third, Information Theory mathematics is applied to the examples and a preliminary methodology in presented for modelling in practice. Fourth, physical artefacts in factory production are reframed as carriers of Information Gain and situated entropy, which may or may not combine as Net Information Gain. Fifth, situated entropy is related to different types of cognitive factories that involve different levels of uncertainty in production operations. Sixth, the need to measure Net Information Gain in the introduction of new technologies for embodied and extended cognition is discussed in relation to a taxonomy for distributed cognition situated in factory production. Overall, modelling of situated entropy is introduced as an opportunity for improving the planning and control of factories that deploy human cognition and cognitive technologies including assembly robotics.


Parasite richness and abundance in insular and mainland feral cats: insularity or density?
Hosts living on islands carry few parasite species, and the prevalence and intensity of directly transmitted parasites are often higher in insular than in mainland populations. However, it is unclear whether density or other features of insular populations can be responsible for the pattern observed. We compared the parasite richness, prevalence and intensity of parasites between 2 feral populations of cats living either at low density on an island (Kerguelen) or at high density on the mainland (Lyon). Parasite richness was higher in Lyon than in Kerguelen, where only Toxocara cati was found. T. cati egg prevalence was higher in Kerguelen (71.1%) than in Lyon (58.0%). Because cat density cannot explain this pattern, we propose that the low number of parasite species, the diet and/or immunity of cats act to increase prevalence in Kerguelen. Moreover, prevalence, intensity and variance-to-mean ratio increased with age and body mass in Kerguelen whereas, in Lyon, prevalence decreased with age and body mass. We hypothesize that the pattern of exposure differs between populations, and that density-dependent parasite mortality is lower in Kerguelen than in Lyon. We discuss the consequences concerning the influence of parasites on insular host populations.


Effect of fipronil on subterranean termite colonies (Isoptera: Rhinotermitidae) in the field.
To assess possible colony-level effects of fipronil, a commonly used nonrepellent termiticide, we conducted a field study of eight houses in the Raleigh, NC, area with infestations of the eastern subterranean termite Reticulitermes flavipes (Kollar) (Isoptera: Rhinotermitidae). We installed an extensive grid of in-ground monitoring stations on each property (mean = 68.6 monitors per property) and collected samples from these stations as well as from mud tubes in the structure and wood debris in the yard for approximately 6 mo. We genotyped all samples by using microsatellite markers to identify the number and locations of colonies present on each property. Houses were treated with either a full treatment (n = 5) or exterior/localized interior treatment (n = 3). After treatment, the monitors were checked monthly for 3 mo and then quarterly for 3 yr to track the fate of colonies. Wood debris in natural areas was checked semiannually for 3 yr. All 11 of the treated colonies (those attacking structures) disappeared within 90 d of treatment and were not found again. These colonies were presumed to be eliminated. In contrast, 60% of untreated colonies (those located > 6 m from the foundation wall at the time of treatment) continued to persist throughout the study, as did 25% of the likely treated colonies (those occupying monitors 0.5 m from the foundation wall where the treatment was applied). Our results provide strong evidence for potent colony wide effects of fipronil on subterranean termites leading to colony suppression and likely colony elimination under field conditions.


Gender and drug differences in antisocial personality disorder.
The relation between childhood behavior disorders (CBD), attentional difficulties (ADD), and antisocial personality disorder (ASP) was examined in a clinical population of alcoholics and polysubstance abusers. Polysubstance abusers reported increased CBD symptomatology, increased attentional problems, a higher rate of ASP, and a greater number of both current and lifetime ASP symptoms relative to alcoholics without polysubstance abuse. An examination of gender effects revealed significant differences on self-reported adult attentional problems, with females endorsing a greater number of items. As a group, females exhibited the highest rate of ASP. Males showed a significant correlation between current ASP symptoms and both attention and conduct problems in early childhood.


Global karst springs hydrograph dataset for research and management of the world's fastest-flowing groundwater.
Karst aquifers provide drinking water for 10% of the world's population, support agriculture, groundwater-dependent activities, and ecosystems. These aquifers are characterised by complex groundwater-flow systems, hence, they are extremely vulnerable and protecting them requires an in-depth understanding of the systems. Poor data accessibility has limited advances in karst research and realistic representation of karst processes in large-scale hydrological studies. In this study, we present World Karst Spring hydrograph (WoKaS) database, a community-wide effort to improve data accessibility. WoKaS is the first global karst springs discharge database with over 400 spring observations collected from articles, hydrological databases and researchers. The dataset's coverage compares to the global distribution of carbonate rocks with some bias towards the latitudes of more developed countries. WoKaS database will ensure easy access to a large-sample of good quality datasets suitable for a wide range of applications: comparative studies, trend analysis and model evaluation. This database will largely contribute to research advancement in karst hydrology, supports karst groundwater management, and promotes international and interdisciplinary collaborations.


Comparative Analysis of Whole-Genome Gene Expression Changes in Cultured Human Embryonic Stem Cells in Response to Low, Clinical Diagnostic Relevant, and High Doses of Ionizing Radiation Exposure.
The biological effects of low-dose ionizing radiation (LDIR) exposure in humans are not comprehensively understood, generating a high degree of controversy in published literature. The earliest stages of human development are known to be among the most sensitive to stress exposures, especially genotoxic stresses. However, the risks stemming from exposure to LDIR, particularly within the clinical diagnostic relevant dose range, have not been directly evaluated in human embryonic stem cells (hESCs). Here, we describe the dynamics of the whole genome transcriptional responses of different hESC lines to both LDIR and, as a reference, high-dose IR (HDIR). We found that even doses as low as 0.05 Gy could trigger statistically significant transient changes in a rather limited subset of genes in all hESCs lines examined. Gene expression signatures of hESCs exposed to IR appear to be highly dose-, time-, and cell line-dependent. We identified 50 genes constituting consensus gene expression signature as an early response to HDIR across all lines of hESC examined. We observed substantial differences in biological pathways affected by either LDIR or HDIR in hESCs, suggesting that the molecular mechanisms underpinning the responses of hESC may fundamentally differ depending on radiation doses.


Increasing the free spectral range of silica waveguide rings for filter applications.
Ring resonators are promising building blocks for developing compact optical filters with arbitrary functions; however, a major challenge for planar waveguide filter implementations is to overcome the limited free spectral range (FSR) for a given core-to-cladding refractive-index difference (D) while maintaining low loss and a large range of coupling ratios. The loss and coupling of rings operating in the whispering-gallery-mode regime were investigated by use of Ge-doped silica waveguides with a low refractive-index difference (D=0.75%) . A FSR of 12 GHz with a loss of 0.36 dB/cm was demonstrated with coupling ratios of 30% (41% optimum).


Deviant Processing in the Primary Somatosensory Cortex.
Stimulus-specific adaptation (SSA) to repetitive stimulation has been proposed to separate behaviorally relevant features from a stream of continuous sensory information. However, the exact mechanisms giving rise to SSA and cortical deviance detection are not well understood. We therefore used an oddball paradigm and multicontact electrodes to characterize single-neuron and local field potential responses to various deviant stimuli across the rat somatosensory cortex. Changing different single-whisker stimulus features evoked robust SSA in individual cortical neurons over a wide range of stimulus repetition rates (0.25-80 Hz). Notably, SSA was weakest in the granular input layer and significantly stronger in the supra- and infragranular layers, suggesting that a major part of SSA is generated within cortex. Moreover, we found a small subset of neurons in the granular layer with a deviant-specific late response, occurring roughly 200 ms after stimulus offset. This late deviant response exhibited true-deviance detection properties that were not explained by depression of sensory inputs. Our results show that deviant responses are actively amplified within cortex and contain an additional late component that is sensitive for context-specific sensory deviations. This strongly implicates deviance detection as a feature of intracortical stimulus processing beyond simple sensory input depression.


The role of UVR and vitamin D on T cells and inflammatory bowel disease.
Vitamin D deficiency is associated with the development of inflammatory bowel disease (IBD). In experimental IBD the targets of vitamin D that result in protection from IBD include gut epithelial cells, innate immune cells, T cells, and the microbiota. Ultraviolet radiation (UVR) induces production of vitamin D in the skin and suppresses T cell responses in the host. There is limited data demonstrating an effect of UVR on experimental IBD but the mechanisms of UVR suppression in IBD have not been defined. There are several shared effects of vitamin D and UVR on T cells including inhibition of proliferation and suppression of IFN-γ and IL-17 producing T cells. Conversely UVR decreases and vitamin D increases IL-4 production from T cells. Together the data suggest that UVR suppression of T cells and potentially IBD are both vitamin D dependent and independent.


Efficacy and safety of ruxolitinib in Asian patients with myelofibrosis.
Myelofibrosis is characterized by progressive cytopenias, bone marrow fibrosis, splenomegaly and severe constitutional symptoms. In the phase 3 Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies, ruxolitinib, a potent Janus kinase 1 (JAK1)/JAK2 inhibitor, provided substantial improvements in splenomegaly, symptoms, quality-of-life measures and overall survival compared with placebo or best available therapy. No assessments of the efficacy and safety of ruxolitinib have been conducted in Asian patients. Here, we describe results from an open-label, single-arm, phase 2 trial evaluating ruxolitinib in Asian patients with myelofibrosis (n = 120). The primary endpoint was met, with 31.7% of patients achieving a ≥ 35% reduction from baseline spleen volume at week 24. As measured by the 7-day Myelofibrosis Symptom Assessment Form v2.0, 49% of patients achieved a ≥ 50% reduction from baseline in total symptom score. Adverse events were consistent with those seen in the COMFORT studies. Ruxolitinib was well tolerated in Asian patients with myelofibrosis and provided substantial reductions in splenomegaly and improvements in symptoms.


Association of elevated fasting glucose with lower patency and increased major adverse limb events among patients with diabetes undergoing infrapopliteal balloon angioplasty.
Diabetes mellitus (DM) is a significant risk factor for loss of patency after endovascular intervention, but the contribution of glycemic control to infrapopliteal artery patency among patients with DM is unknown. All percutaneous infrapopliteal interventions among patients with DM from 2006 to 2013 were reviewed and pre-procedure fasting blood glucose (FBG) was recorded. The primary endpoint was primary patency at 1 year as determined by duplex ultrasound. A total of 309 infrapopliteal lesions in 149 patients with DM were treated with balloon angioplasty during the study period. The median FBG was 144 mg/dL. At 1 year, the rate of primary patency was 16% for patients with FBG above the median, compared to 46% for patients with FBG below the median (hazard ratio (HR) 1.82 for FBG ≥144, p=0.005). Amputation rates at 1 year trended higher among patients with high versus low FBG (24% vs 15%, p=0.1). One year major adverse limb event rates were also higher for patients with high versus low FBG (35% vs 23%, p=0.05). Although patients with high FBG were more likely to have insulin-requiring DM (73% vs 50%, p=0.003) the association of high FBG with loss of primary patency remained significant even after adjusting for insulin use as well as other lesion-specific characteristics (adjusted HR 1.8, 95% CI 1.2-2.8). In conclusion, high fasting blood glucose at the time of infrapopliteal balloon angioplasty is associated with significantly decreased primary patency and may also be a risk factor for major adverse limb events among patients with a threatened limb.


Prediction of fine-tuned promoter activity from DNA sequence.
The quantitative prediction of transcriptional activity of genes using promoter sequence is fundamental to the engineering of biological systems for industrial purposes and understanding the natural variation in gene expression. To catalyze the development of new algorithms for this purpose, the Dialogue on Reverse Engineering Assessment and Methods (DREAM) organized a community challenge seeking predictive models of promoter activity given normalized promoter activity data for 90 ribosomal protein promoters driving expression of a fluorescent reporter gene. By developing an unbiased modeling approach that performs an iterative search for predictive DNA sequence features using the frequencies of various k-mers, inferred DNA mechanical properties and spatial positions of promoter sequences, we achieved the best performer status in this challenge. The specific predictive features used in the model included the frequency of the nucleotide G, the length of polymeric tracts of T and TA, the frequencies of 6 distinct trinucleotides and 12 tetranucleotides, and the predicted protein deformability of the DNA sequence. Our method accurately predicted the activity of 20 natural variants of ribosomal protein promoters (Spearman correlation r = 0.73) as compared to 33 laboratory-mutated variants of the promoters (r = 0.57) in a test set that was hidden from participants. Notably, our model differed substantially from the rest in 2 main ways: i) it did not explicitly utilize transcription factor binding information implying that subtle DNA sequence features are highly associated with gene expression, and ii) it was entirely based on features extracted exclusively from the 100 bp region upstream from the translational start site demonstrating that this region encodes much of the overall promoter activity. The findings from this study have important implications for the engineering of predictable gene expression systems and the evolution of gene expression in naturally occurring biological systems.


Bridging the "two cultures" in ethnopharmacology: barriers against interdisciplinarity in postgraduate education.
As significant contributors to the generation, dissemination and publication of scientific knowledge, graduate students have considerable leverage on publication trends and the future direction of ethnopharmacology. The rigid discipline-oriented framework of academia is often cited as responsible for impeding interdisciplinarity, particularly for fields such as ethnopharmacology which span both the natural and social science domains. Funding opportunities, funding eligibility periods, time-to-degree patterns and departmental expectations and requirements for graduate students enrolled in the natural sciences are considerably different than for those in the social sciences. Consequently, adequate acquisition of ethnographic data is often compromised. Encouraging students to think across disciplines, cross-disciplinary collaboration, and flexibility in regards to the time and financial constraints imposed by departments and funding agencies would increase the likelihood of contextualizing bioscientific data with adequate traditional empirical knowledge, and ultimately embrace the core objectives on which the JEP was conceived.


Effect of ethacrynic acid on aqueous outflow dynamics in monkeys.
To determine the long-term effect of ethacrynic acid (ECA) on aqueous outflow dynamics in ocular normotensive monkeys. (1) Twelve cynomolgus monkeys received 10 microliters of 2.5 mM (= 7.5 micrograms) ECA intracamerally in one eye, vehicle in the other; outflow facility (perfusion) was determined at 1 hour, 24 hours, or 1 week, and intraocular pressure (IOP; applanation) at 24 hours, 1 week, and 6 to 7 weeks later. Six other cynomolgi received 10 microliters of 0.13 or 1.3 mM phalloidin in one eye 45 minutes before receiving ECA OU; facility was measured 1 hour after ECA. (2) Groups of five rhesus monkeys underwent intracameral injection of 2.5, 5.0, or 10 micrograms ECA in one eye, vehicle in the other, with IOP measured hours to weeks thereafter. (3) Five rhesus monkeys received 540 micrograms of ECA unilaterally as a 30-microliter topical drop once daily for 4 days. On the first and fourth treatment days, baseline IOP, pupil diameter, and refraction were measured immediately before and again at 2, 4, and 7 hours after topical treatment. (1) ECA divided by vehicle facility averaged 1.83 +/- 0.23 (SEM) (P < 0.02, n = 6), 1.50 +/- 0.27 (P < 0.11, n = 7), and 1.05 +/- 0.10 (n = 7) at 1 hour, 24 hours, and 1 week, respectively. IOP was 1 to 2 mm Hg lower in ECA eyes 24 hours (P < 0.05, n = 5) and 6 to 7 weeks (P < 0.05, n = 7) after treatment. Phalloidin did not diminish the 1-hour ECA facility effect. (2) Five (but not 2.5 or 10) micrograms of ECA lowered IOP 1 to 3 mm Hg, starting at 2 hours and lasting up to 48 hours. The maximum ECA effect (-2.6 +/- 0.25 mm Hg; P < 0.001, n = 5) occurred at 4 hours. IOP, corneal thickness and endothelial cell count, and anterior chamber depth were not significantly different 8 weeks after 5 micrograms ECA or vehicle. (3) Once-daily unilateral topical application of 540 micrograms of ECA induced no change in IOP, refraction, or pupil diameter compared to contralateral vehicle-treated control eyes. There were no significant ECA-related ocular bio-microscopic abnormalities. ECA may lower IOP and increase outflow facility longer than previously thought, but not by affecting meshwork actin filaments.


Host vascular endothelial growth factor is trophic for Plasmodium falciparum-infected red blood cells.
Plasmodium falciparum, the protozoan parasite responsible for severe malaria infection, undergoes a complex life cycle. Infected red blood cells (iRBC) sequester in host cerebral microvessels, which underlies the pathology of cerebral malaria. Using immunohistochemistry on post mortem brain samples, we demonstrated positive staining for vascular endothelial growth factor (VEGF) on iRBC. Confocal microscopy of cultured iRBC revealed accumulation of VEGF within the parasitophorous vacuole, expression of host VEGF-receptor 1 and activated VEGF-receptor 2 on the surface of iRBC, but no accumulation of VEGF receptors within the iRBC. Addition of VEGF to parasite cultures had a trophic effect on parasite growth and also partially rescued growth of drug treated parasites. Both these effects were abrogated when parasites were grown in serum-free medium, suggesting a requirement for soluble VEGF receptor. We conclude that P. falciparum iRBC can bind host VEGF-R on the erythrocyte membrane and accumulate host VEGF within the parasitophorous vacuole, which may have a trophic effect on parasite growth.


Mental health care in Nepal: current situation and challenges for development of a district mental health care plan.
Globally mental health problems are a serious public health concern. Currently four out of five people with severe mental illness in Low and Middle Income Countries (LMIC) receive no effective treatment. There is an urgent need to address this enormous treatment gap. Changing the focus of specialist mental health workers (psychiatrists and psychologists) from only service delivery to also designing and managing mental health services; building clinical capacity of the primary health care (PHC) workers, and providing supervision and quality assurance of mental health services may help in scaling up mental health services in LMICs. Little is known however, about the mental health policy and services context for these strategies in fragile-state settings, such as Nepal. A standard situation analysis tool was developed by the PRogramme for Improving Mental health carE (PRIME) consortium to systematically analyze and describe the current gaps in mental health care in Nepal, in order to inform the development of a district level mental health care plan (MHCP). It comprised six sections; general information (e.g. population, socio-economic conditions); mental health policies and plans; mental health treatment coverage; district health services; and community services. Data was obtained from secondary sources, including scientific publications, reports, project documents and hospital records. Mental health policy exists in Nepal, having been adopted in 1997, but implementation of the policy framework has yet to begin. In common with other LMICs, the budget allocated for mental health is minimal. Mental health services are concentrated in the big cities, with 0.22 psychiatrists and 0.06 psychologists per 100,000 population. The key challenges experienced in developing a district level MHCP included, overburdened health workers, lack of psychotropic medicines in the PHC, lack of mental health supervision in the existing system, and lack of a coordinating body in the Ministry of Health and Population (MoHP). Strategies to overcome these challenges included involvement of MoHP in the process, especially by providing psychotropic medicines and appointing a senior level officer to facilitate project activities, and collaboration with National Health Training Centers (NHTC) in training programs. This study describes many challenges facing mental health care in Nepal. Most of these challenges are not new, yet this study contributes to our understanding of these difficulties by outlining the national and district level factors that have a direct influence on the development of a district level mental health care plan.


Patterns of genetic variation in the endangered European mink (Mustela lutreola L., 1761).
The European mink (Mustela lutreola, L. 1761) is a critically endangered mustelid, which inhabits several main river drainages in Europe. Here, we assess the genetic variation of existing populations of this species, including new sampling sites and additional molecular markers (newly developed microsatellite loci specific to European mink) as compared to previous studies. Probabilistic analyses were used to examine genetic structure within and between existing populations, and to infer phylogeographic processes and past demography. According to both mitochondrial and nuclear microsatellite markers, Northeastern (Russia, Estonia and Belarus) and Southeastern (Romania) European populations showed the highest intraspecific diversity. In contrast, Western European (France and Spain) populations were the least polymorphic, featuring a unique mitochondrial DNA haplotype. The high differentiation values detected between Eastern and Western European populations could be the result of genetic drift in the latter due to population isolation and reduction. Genetic differences among populations were further supported by Bayesian clustering and two main groups were confirmed (Eastern vs. Western Europe) along with two contained subgroups at a more local scale (Northeastern vs. Southeastern Europe; France vs. Spain). Genetic data and performed analyses support a historical scenario of stable European mink populations, not affected by Quaternary climate oscillations in the Late Pleistocene, and posterior expansion events following river connections in both North- and Southeastern European populations. This suggests an eastern refuge during glacial maxima (as already proposed for boreal and continental species). In contrast, Western Europe was colonised more recently following either natural expansions or putative human introductions. Low levels of genetic diversity observed within each studied population suggest recent bottleneck events and stress the urgent need for conservation measures to counteract the demographic decline experienced by the European mink.


Rediscovery of the Australian strain of infectious hypodermal and haematopoietic necrosis virus.
In this study we rediscovered and verified the presence of an infectious hypodermal and haematopoietic necrosis virus (IHHNV) strain amongst cultured penaeid prawns Penaeus monodon from 1993 in Australia on the basis of a PCR analysis with IHHNV specific primers and sequencing of the resulting amplicons. A total of 7 previously published diagnostic primers specific to IHHNV were tested against Australian penaeid prawns and only 1 elicited a positive IHHNV PCR result with 16 out of 20 Australian P. monodon samples examined. In comparison, all 7 primers produced IHHNV-positive amplicons from the New Caledonian control samples. Analysis and comparison of the 392 bp fragment derived from the Australian IHHNV strain (AY590120) with other geographical isolates revealed that the Madagascar isolate shared the highest nucleotide similarity (96.2%) and the Hawaiian and New Caledonian strain the highest nucleotide divergence (90.1 and 90.3% respectively). The high nucleotide variation observed between the Australian and Hawaiian strains provides an explanation for the lack of IHHNV detection amongst Australian prawns with published IHHNV PCRs and commercially available gene probes as they are primarily designed on the basis of the Hawaiian strain (AF218266). Results indicated that IHHNV has been present in Australia for a long (geological and contemporary) time and that the virus is endemic in penaeid prawns in the Australian environment.


Candida bracarensis detected among isolates of Candida glabrata by peptide nucleic acid fluorescence in situ hybridization: susceptibility data and documentation of presumed infection.
Molecular taxonomic studies have revealed new Candida species among phenotypically delineated species, the best example being Candida dubliniensis. This study was designed to determine the occurrence of two new molecularly defined species, Candida bracarensis and Candida nivariensis, which are closely related to and identified as Candida glabrata by phenotypic assays. A total of 137 recent clinical isolates of C. glabrata identified by phenotypic characteristics was tested with C. bracarensis and C. nivariensis species-specific peptide nucleic acid fluorescence in situ hybridization probes. Three of 137 (2.2%) isolates were positive with the C. bracarensis probe, whereas the control strain, but none of the clinical isolates, was positive with the C. nivariensis probe. D1/D2 sequencing confirmed the identification of the three isolates as representing C. bracarensis. Clinically, one C. bracarensis isolate was recovered from a presumed infection, a polymicrobial pelvic abscess in a patient with perforated diverticulitis. The other two isolates were recovered from two adult oncology patients who were only colonized. C. bracarensis was white on CHROMagar Candida, had variable API-20C patterns that overlapped with C. nivariensis and some C. glabrata isolates, and had variable results with a rapid trehalose assay. Interestingly, an isolate from one of the colonized oncology patients was resistant to fluconazole, itraconazole, voriconazole, and posaconazole in vitro. In summary, C. bracarensis was detected among clinical isolates of C. glabrata, while C. nivariensis was not. One C. bracarensis isolate causing a presumed deep infection was recovered, and another isolate was azole resistant. Whether clinical laboratories should identify C. bracarensis will require more data.


Indicaxanthin inhibits NADPH oxidase (NOX)-1 activation and NF-κB-dependent release of inflammatory mediators and prevents the increase of epithelial permeability in IL-1β-exposed Caco-2 cells.
Dietary redox-active/antioxidant phytochemicals may help control or mitigate the inflammatory response in chronic inflammatory bowel disease (IBD). In the present study, the anti-inflammatory activity of indicaxanthin (Ind), a pigment from the edible fruit of cactus pear (Opuntia ficus-indica, L.), was shown in an IBD model consisting of a human intestinal epithelial cell line (Caco-2 cells) stimulated by IL-1β, a cytokine known to play a major role in the initiation and amplification of inflammatory activity in IBD. The exposure of Caco-2 cells to IL-1β brought about the activation of NADPH oxidase (NOX-1) and the generation of reactive oxygen species (ROS) to activate intracellular signalling leading to the activation of NF-κB, with the over-expression of inflammatory enzymes and release of pro-inflammatory mediators. The co-incubation of the cells with Ind, at a nutritionally relevant concentration (5-25 μM), and IL-1β prevented the release of the pro-inflammatory cytokines IL-6 and IL-8, PGE2 and NO, the formation of ROS and the loss of thiols in a dose-dependent manner. The co-incubation of the cells with Ind and IL-1β also prevented the IL-1β-induced increase of epithelial permeability. It was also shown that the activation of NOX-1 and NF-κB was prevented by Ind and the expression of COX-2 and inducible NO synthase was reduced. The uptake of Ind in Caco-2 cell monolayers appeared to be unaffected by the inflamed state of the cells. In conclusion, our findings suggest that the dietary pigment Ind may have the potential to modulate inflammatory processes at the intestinal level.


Complement protein C1q modulates neurite outgrowth in vitro and spinal cord axon regeneration in vivo.
Traumatic injury to CNS fiber tracts is accompanied by failure of severed axons to regenerate and results in lifelong functional deficits. The inflammatory response to CNS trauma is mediated by a diverse set of cells and proteins with varied, overlapping, and opposing effects on histological and behavioral recovery. Importantly, the contribution of individual inflammatory complement proteins to spinal cord injury (SCI) pathology is not well understood. Although the presence of complement components increases after SCI in association with axons and myelin, it is unknown whether complement proteins affect axon growth or regeneration. We report a novel role for complement C1q in neurite outgrowth in vitro and axon regrowth after SCI. In culture, C1q increased neurite length on myelin. Protein and molecular assays revealed that C1q interacts directly with myelin associated glycoprotein (MAG) in myelin, resulting in reduced activation of growth inhibitory signaling in neurons. In agreement with a C1q-outgrowth-enhancing mechanism in which C1q binding to MAG reduces MAG signaling to neurons, complement C1q blocked both the growth inhibitory and repulsive turning effects of MAG in vitro. Furthermore, C1q KO mice demonstrated increased sensory axon turning within the spinal cord lesion after SCI with peripheral conditioning injury, consistent with C1q-mediated neutralization of MAG. Finally, we present data that extend the role for C1q in axon growth and guidance to include the sprouting patterns of descending corticospinal tract axons into spinal gray matter after dorsal column transection SCI.


Improving antibiotic prescribing in acute respiratory tract infections: cluster randomised trial from Norwegian general practice (prescription peer academic detailing (Rx-PAD) study).
To assess the effects of a multifaceted educational intervention in Norwegian general practice aiming to reduce antibiotic prescription rates for acute respiratory tract infections and to reduce the use of broad spectrum antibiotics. Cluster randomised controlled study. Existing continuing medical education groups were recruited and randomised to intervention or control. 79 groups, comprising 382 general practitioners, completed the interventions and data extractions. The intervention groups had two visits by peer academic detailers, the first presenting the national clinical guidelines for antibiotic use and recent research evidence on acute respiratory tract infections, the second based on feedback reports on each general practitioner's antibiotic prescribing profile from the preceding year. Regional one day seminars were arranged as a supplement. The control arm received a different intervention targeting prescribing practice for older patients. Prescription rates and proportion of non-penicillin V antibiotics prescribed at the group level before and after the intervention, compared with corresponding data from the controls. In an adjusted, multilevel model, the effect of the intervention on the 39 intervention groups (183 general practitioners) was a reduction (odds ratio 0.72, 95% confidence interval 0.61 to 0.84) in prescribing of antibiotics for acute respiratory tract infections compared with the controls (40 continuing medical education groups with 199 general practitioners). A corresponding reduction was seen in the odds (0.64, 0.49 to 0.82) for prescribing a non-penicillin V antibiotic when an antibiotic was issued. Prescriptions per 1000 listed patients increased from 80.3 to 84.6 in the intervention arm and from 80.9 to 89.0 in the control arm, but this reflects a greater incidence of infections (particularly pneumonia) that needed treating in the intervention arm. The intervention led to improved antibiotic prescribing for respiratory tract infections in a representative sample of Norwegian general practitioners, and the courses were feasible to the general practitioners. Clinical trials NCT00272155.


Elimination half-life of intravenously administered equine cardiac troponin I in healthy ponies.
To date, no information is available on the true biological elimination half-life (T(1/2) ) of cardiac troponin I (cTnI) in the equine species. Such data are required to better evaluate the optimal time to acquire the cTnI sample following acute myocardial injury. To determine the T(1/2) of equine cTnI. Four healthy ponies received i.v. injections of recombinant equine cTnI. Plasma cTnI concentrations were measured with a point-of-care cTnI analyser at multiple time points after injection. Standard pharmacokinetic analysis was performed to establish the T(1/2) of cTnI. The average T(1/2) of cTnI was determined to be 0.47 h using a single rate elimination model. The elimination of recombinant equine cTnI following i.v. administration is very rapid. Establishing the T(1/2 ) of troponin provides critical information in understanding the clinical application of this cardiac biomarker in equine practice.


Effect of Sclerotial Water Content on Carpogenic Germination of Sclerotinia sclerotiorum.
The relationship between moisture content and carpogenic germination (CG) of Sclerotinia sclerotiorum sclerotia and the dynamics of sclerotial water imbibition were studied in a controlled environment. The study was conducted using laboratory-produced sclerotia from seven S. sclerotiorum isolates. The quantity and rate of water imbibition by three sizes of sclerotia was determined gravimetrically in silty clay, sandy loam, and sandy soils maintained at 100, 75, 50, and 25% of soil saturation and in distilled water. Smaller sclerotia imbibed water at a significantly faster rate (P = 0.05) than larger sclerotia in water and in soil at all saturation percentages. When buried in soil, small, medium, and large sclerotia were fully saturated within 5, 15, and 25 h, respectively, in all three soil types and moisture percentages. The effect of sclerotia moisture content on CG was evaluated on sclerotia maintained at 95 to 100, 70 to 80, 40 to 50, and 20 to 30% of their water saturation capacity using cool mist humidifiers. Sclerotial moisture content significantly influenced CG (P = 0.05). Maximum CG was observed on fully saturated sclerotia, while no CG was observed below 70 to 80% of saturation. These findings help explain S. sclerotiorum's ability to produce apothecia in soils with relatively low moisture levels.


Association of Muscle Weakness With Post-Fracture Mortality in Older Men and Women: A 25-Year Prospective Study.
Osteoporotic fracture increases the risk of premature mortality. Muscle weakness is associated with both increased fracture risk and low bone mineral density (BMD). However, the role of muscle strength in post-fracture mortality is not well understood. This study examines the change of muscle strength measured at quadriceps (QS) before and after fracture and defines the relationship between muscle strength and post-fracture mortality. The study involved 889 women and 295 men (who were participating in the Dubbo Osteoporosis Study) who had at least one low-trauma fracture (ascertained from X-ray reports) after the age of 50 years. Median follow-up time was 11 years (range 1 to 24). To determine the change in muscle strength before and after a fracture, we selected a subset of 344 women and 99 men who had had at least two muscle strength measurements before the fracture event and a subset of 407 women and 105 men who had had at least two measurements after the fracture. During the follow-up period, 366 (41.2%) women and 150 (50.9%) men died. The annual rate of decrease in height-adjusted muscle strength before fracture was 0.27 kg/m (1.85%) in women and 0.40 kg/m (1.79%) in men. Strength loss after fracture was not significantly different from that before fracture. In women, after adjusting for baseline age and BMD, each SD (5 kg/m) lower height-adjusted pre- and post-fracture quadriceps strength was associated with a 27% (hazard ratio [HR] = 1.27; 95% confidence interval [CI] 1.07, 1.50) and 18% (HR = 1.18; 95% CI 1.01, 1.38) increase in post-fracture mortality risk, respectively. Similarly, in men, each SD (5 kg/m) lower height-adjusted pre- and post-fracture QS was associated with increased mortality before fracture (HR = 1.33; 95% CI 1.09, 1.63) and after fracture (HR = 1.43; 95% CI 1.16, 1.78). Muscle weakness accounted for 15% (95% CI 0.05, 0.24) of premature deaths after fracture in women and 23% (95% CI 0.11, 0.35) in men. These results indicate that in the older individuals, lower muscle strength is an independent risk factor for post-fracture mortality. © 2017 American Society for Bone and Mineral Research.


An attempt to reproduce a previous meta-analysis and a new analysis regarding the impact of directly observed therapy on tuberculosis treatment outcomes.
Directly observed therapy (DOT) is almost universally used for the treatment of TB. Several meta-analyses using different methods have assessed the effectiveness of DOT compared to self-administered therapy (SAT). The results of these meta-analyses often conflict with some concluding DOT is superior and others that there is little or no difference. Meta-analyses can guide policymaking, but such analyses must be reliable. To assess the validity of a previous meta-analysis, we tried to reproduce it. We encountered problems with the previous analysis that did not allow for a meaningful reproduction. We describe the issues we encountered here. We then performed a new meta-analysis comparing the treatment outcomes of adults given treatment with SAT versus DOT. Outcomes in the new analysis are loss to follow-up, treatment failure, cure, treatment completed, and all-cause mortality. All data, documentation, and code used to generate our results is provided. Our new analysis included four randomized and three observational studies with 1603 and 1626 individuals respectively. The pooled relative risks (RR) are as follows: Lost to follow-up (RR = 1.2, 95% CI 0.9, 1.7), Treatment Failure (RR = 1.1, 95% CI 0.6, 2), Cure (RR = 0.9, 95% CI 0.8, 1.1), Treatment Completion (RR = 1, 95% CI 0.9, 1.1), Mortality (RR = 0.9, 95% CI 0.6, 1.3). Based on data from our new meta-analysis, the magnitude of the difference between DOT and SAT for all reported outcomes is small, and none of the differences are statistically significant.


Separating the reinforcing and discriminative properties of brief-stimulus presentations in second-order schedules.
Pigeons' responses were maintained under multiple schedules to study properties of briefly presented stimuli. Responses in one component produced food according to a second-order schedule with fixed-interval components in which food or a brief stimulus occurred with equal probability. In the second component responses produced only the brief stimulus under a fixed-ratio schedule. Under various conditions the brief stimulus in the first component was (a) paired with food, (b) not paired with food, (c) partially omitted, or (d) scheduled simultaneously with the second-order schedule under an independent variable-interval schedule. Paired and nonpaired brief stimuli maintained similar response patterning in the second-order schedule. However, only paired stimuli maintained responses in the second component. The data suggest that nonpaired brief stimuli engender response patterning in second-order schedules as a result of their discriminative properties. When the stimulus is paired with food, these discriminative properties sometime mask a reinforcement effect, and no change in response patterning is observed. When the discriminative properties of the brief stimulus are absent, the reinforcing effects of pairing the brief stimulus with food may be observed.


MicroRNAs That Contribute to Coordinating the Immune Response in Drosophila melanogaster.
Small noncoding RNAs called microRNAs (miRNAs) have emerged as post-transcriptional regulators of gene expression related to host defenses. Here, we have used Drosophila melanogaster to explore the contribution of individual or clusters of miRNAs in countering systemic Candida albicans infection. From a total of 72 tested, we identify 6 miRNA allelic mutant backgrounds that modulate the survival response to infection and the ability to control pathogen number. These mutants also exhibit dysregulation of the Toll pathway target transcripts Drosomycin (Drs) and Immune-Induced Molecule 1 (IM1). These are characteristics of defects in Toll signaling, and consistent with this, we demonstrate dependency for one of the miRNA mutants on the NF-κΒ homolog Dif. We also quantify changes in the miRNA expression profile over time in response to three pathogen types, and identify 13 mature miRNA forms affected by pathogens that stimulate Toll signaling. To complement this, we provide a genome-wide map of potential NF-κB sites in proximity to miRNA genes. Finally, we demonstrate that systemic C. albicans infection contributes to a reduction in the total amount of branch-chained amino acids, which is miRNA-regulated. Overall, our data reveal a new layer of miRNA complexity regulating the fly response to systemic fungal infection.


Comparison of international normalized ratio audit parameters in patients enrolled in GARFIELD-AF and treated with vitamin K antagonists.
Vitamin K antagonist (VKA) therapy for stroke prevention in atrial fibrillation (AF) requires monitoring of the international normalized ratio (INR). We evaluated the agreement between two INR audit parameters, frequency in range (FIR) and proportion of time in the therapeutic range (TTR), using data from a global population of patients with newly diagnosed non-valvular AF, the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF). Among 17 168 patients with 1-year follow-up data available at the time of the analysis, 8445 received VKA therapy (±antiplatelet therapy) at enrolment, and of these patients, 5066 with ≥3 INR readings and for whom both FIR and TTR could be calculated were included in the analysis. In total, 70 905 INRs were analysed. At the patient level, TTR showed higher values than FIR (mean, 56·0% vs 49·8%; median, 59·7% vs 50·0%). Although patient-level FIR and TTR values were highly correlated (Pearson correlation coefficient [95% confidence interval; CI], 0·860 [0·852-0·867]), estimates from individuals showed widespread disagreement and variability (Lin's concordance coefficient [95% CI], 0·829 [0·821-0·837]). The difference between FIR and TTR explained 17·4% of the total variability of measurements. These results suggest that FIR and TTR are not equivalent and cannot be used interchangeably.


Barriers for nurses' participation in and utilisation of clinical research in three hospitals within the Kumasi Metropolis, Ghana.
Scientific research results are a necessary base for high quality nursing practice. The level of implementation of research in the clinical setting, including nurses' participation in and knowledge of research results, have gained considerable attention internationally. However, the remarkable international increase of such studies does not apply to the Ghanaian context. We therefore set out to evaluate the degree of involvement of nurses in research, as well as their utilization patterns of research findings in Ghana. Objectives: the study sought to investigate the proportion of nurses involved in clinical research as well as barriers for nurses' participation and utilization of research findings, within the Kumasi Metropolis area, Ghana. A descriptive and analytical cross-sectional study design was used in this study. A 47 item questionnaire elicited data on 158 participants' demographics, the proportion and the barriers to participation, which was then analyzed using SSPS version 17 software. Qualitative interviews with key informants complemented quantitative survey data. In-depth interviews with nurse managers at the hospitals in focus was conducted and analyzed thematically. The study shows that 36.1% of the nurses, included in the study, had participated in research and only 25.3% of these had (knowingly) used specific research results in clinical practice. However, the level of research participation differed greatly between nurses working at different hospitals. Nurses' participation in clinical research was shown to be associated with their perception of benefit of research to practice as well as their understanding of time as a factor for them engaging in reading scientific articles. In addition, barriers associated with nurses' integration of research findings into the daily practice was their perceived lack of support from the collegium and their perception of research as not part of the nursing role. Findings from the study suggest that there is a need to create institutional support to facilitate and encourage nurses' participation in research, yet also to formalize nurses' continuous professional development. This, could change nurses' attitudes towards research, and contribute to improving health care as it would increase nurses' role as agents for evidence based clinical practice.


Hyperphosphatasemia and concurrent adrenal gland dysfunction in apparently healthy Scottish Terriers.
To determine causes of hyperphosphatasemia (high serum alkaline phosphatase [ALP] activity) in apparently healthy Scottish Terriers. Prospective case-controlled study. 34 apparently healthy adult Scottish Terriers (17 with and 17 without hyperphosphatasemia). Serum activities for 3 isoforms (bone, liver, and corticosteroid) of ALP were measured. Concentrations of cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, estradiol, and aldosterone were measured before and after cosyntropin administration (ie, ACTH; 5 microg/kg [2.27 microg/lb], IM). Liver biopsy specimens from 16 dogs (11 with and 5 without hyperphosphatasemia) were evaluated histologically. In dogs with hyperphosphatasemia, the corticosteroid ALP isoform comprised a significantly higher percentage of total ALP activity, compared with the percentage in dogs without hyperphosphatasemia (mean +/- SE, 69 +/- 5.0% and 17 +/- 3.8%, respectively). In 6 dogs with hyperphosphatasemia, but none without, serum cortisol concentrations exceeded reference intervals after ACTH stimulation. Six dogs with and 15 without hyperphosphatasemia had increased concentrations of >or = 1 noncortisol steroid hormone after ACTH stimulation. Serum ALP activity was correlated with cortisol and androstenedione concentrations (r = 0.337 and 0.496, respectively) measured after ACTH stimulation. All dogs with and most without hyperphosphatasemia had abnormal hepatocellular reticulation typical of vacuolar hepatopathy. Subjectively, hepatocellular reticulation was more severe and widespread in hyperphosphatasemic dogs, compared with that in nonhyperphosphatasemic dogs. Hyperphosphatasemia in apparently healthy Scottish Terriers was most likely attributable to hyperadrenocorticism on the basis of exaggerated serum biochemical responses to ACTH administration and histologic hepatic changes, but none of the dogs had clinical signs of hyperadrenocorticism.


What birthweight percentile is associated with optimal perinatal mortality and childhood education outcomes?
Small for gestational age, defined as birthweight <10th percentile for gestational age, is known to be associated with clinically meaningful impairments in health and development. The effects of variation within the normal range of birthweight percentile on perinatal mortality and childhood education remain less well defined. We sought to quantify the association among birthweight percentile, perinatal mortality, and educational outcomes and to determine the optimal birthweight percentile for those outcomes in Aboriginal and non-Aboriginal Australian children. This was a retrospective cohort study. Perinatal data for all children born in the Northern Territory, Australia, from 1999 through 2008 were linked to measures of educational attainment at age 8-9 years. Multivariable analysis was used to determine the optimal birthweight percentile for low perinatal mortality and high reading and numeracy scores. The birth cohort contained 35,239 births (42% Aboriginal), of which 11,214 had linked and valid education records. Median birthweight percentile was 29.2 in Aboriginal infants and 44.0 in non-Aboriginal infants. The odds of perinatal mortality decreased by 4% with each 1-percentile increase birthweight percentile overall (adjusted odds ratio, 0.96; P = .000) and lowest mortality rates were at the 61st and 78th percentile in Aboriginal and non-Aboriginal infants, respectively. Although birthweights <10th percentile were associated with greatly increased odds of perinatal mortality, the increased risk extended well beyond this cut-off. Birthweight percentile was also positively correlated with scores in reading (P = .000) and numeracy (P = .000). In non-Aboriginal children, reading and numeracy scores peaked at the 66th percentile, but for Aboriginal children there was continuous benefit with increasing birthweight percentile. Birthweight percentile explained 1% of the variation in education outcomes, with much greater variation explained by other perinatal and sociodemographic factors. Birthweights between the 50th-93rd percentiles were most consistently associated with both low perinatal mortality and high reading and numeracy scores, suggesting that small for gestational age does not sufficiently capture the risks associated with variation in fetal growth. Our data indicate that the effect of birthweight percentile accounts for 1% of variation in perinatal and education outcomes.


Xenopus oocytes injected with rat uterine RNA express very slowly activating potassium currents.
Under the influence of estrogen, uterine smooth muscle becomes highly excitable, generating spontaneous and prolonged bursts of action potentials. In a study of the mechanisms by which this transition in excitability occurs, polyadenylated RNA from the uteri of estrogen-treated rats was injected into Xenopus oocytes. The injected oocytes expressed a novel voltage-dependent potassium current. This current was not observed in oocytes injected with RNA from several other excitable tissues, including rat brain and uterine smooth muscle from ovariectomized rats not treated with estrogen. The activation of this current on depolarization was exceptionally slow, particularly for depolarizations from relatively negative membrane potentials. Such a slowly activating channel may play an important role in the slow, repetitive bursts of action potentials in the myometrium.


Distinct neural signatures of cognitive subtypes of dyslexia with and without phonological deficits.
Developmental dyslexia can be distinguished as different cognitive subtypes with and without phonological deficits. However, despite some general agreement on the neurobiological basis of dyslexia, the neurofunctional mechanisms underlying these cognitive subtypes remain to be identified. The present BOLD fMRI study thus aimed at investigating by which distinct and/or shared neural activation patterns dyslexia subtypes are characterized. German dyslexic fourth graders with and without deficits in phonological awareness and age-matched normal readers performed a phonological decision task: does the auditory word contain the phoneme/a/? Both dyslexic subtypes showed increased activation in the right cerebellum (Lobule IV) compared to controls. Subtype-specific increased activation was systematically found for the phonological dyslexics as compared to those without this deficit and controls in the left inferior frontal gyrus (area 44: phonological segmentation), the left SMA (area 6), the left precentral gyrus (area 6) and the right insula. Non-phonological dyslexics revealed subtype-specific increased activation in the left supramarginal gyrus (area PFcm; phonological storage) and angular gyrus (area PGp). The study thus provides the first direct evidence for the neurobiological grounding of dyslexia subtypes. Moreover, the data contribute to a better understanding of the frequently encountered heterogeneous neuroimaging results in the field of dyslexia.


Retrospective Analysis of Patients With Prostate Cancer Initiating GnRH Agonists/Antagonists Therapy Using a German Claims Database: Epidemiological and Patient Outcomes.
Objective: The objective of this study was to obtain real-world information on gonadotropin-releasing hormone agonist/antagonist (GnRHa) therapy in patients with advanced prostate cancer (PCa). Materials and methods: Anonymized, routine healthcare claims data from approx. 75 German statutory health insurance funds from 2010-2015 (n = 4,205,227) were analyzed. Patients had an enrolment of 1 year before GnRHa, 1 index quarter of initial GnRHa prescription and ≥2 years of follow-up. Results: In total, 2,382 patients with PCa were eligible. The most frequent index therapy was leuprolide in 56.6%. The rank order of PCa comorbidity prevalence was consistent over time (% at index and 3-years of follow-up): hypertension (71.5; 85.0), hyperlipidemia (45.2; 60.8), cardiovascular disease (CVD) (35.7; 54.1), and diabetes (28.3; 36.2). Comparing pooled therapy classes (agonists, hybrids, and antagonist), no significant differences in the incidence of CVD or diabetes were observed. For hypertension, there was a significant increase for agonists (16.4%) compared to antagonists (6.9%, p = 0.022) and leuprolide hybrid group (11.6%, p = 0.006). During the follow-up period 23.9% of all PCa patients died. There were no significant differences concerning mortality rate and discontinuation rates between the cohorts. In total, 11.2% of all patients discontinued GnRHa after first prescription; the mean time to first switch to another GnRHa therapy was 100 days earlier for hybrids than for agonists (p = 0.016). Conclusion: This comparative retrospective analysis provides real-world information about healthcare characteristics and treatment patterns, highlighting the impact of different GnRHa on clinical outcomes for patients with advanced PCa in Germany.


Thermodynamic and functional characterization of the periplasmic triheme cytochrome PpcA from Geobacter metallireducens.
The Geobacter metallireducens bacterium can couple the oxidation of a wide range of compounds to the reduction of several extracellular electron acceptors, including pollutants or electrode surfaces for current production in microbial fuel cells. For these reasons, G. metallireducens are of interest for practical biotechnological applications. The use of such electron acceptors relies on a mechanism that permits electrons to be transferred to the cell exterior. The cytochrome PpcA from G. metallireducens is a member of a family composed of five periplasmic triheme cytochromes, which are important to bridge the electron transfer from the cytoplasmic donors to the extracellular acceptors. Using NMR and visible spectroscopic techniques, a detailed thermodynamic characterization of PpcA was obtained, including the determination of the heme reduction potentials and their redox and redox-Bohr interactions. These parameters revealed unique features for PpcA from G. metallireducens compared with other triheme cytochromes from different microorganisms, namely the less negative heme reduction potentials and concomitant functional working potential ranges. It was also shown that the order of oxidation of the hemes is pH-independent, but the protein is designed to couple e-/H+ transfer exclusively at physiological pH.


Regulation of cancer stem cells by RING finger ubiquitin ligases.
Like normal stem cells, cancer stem cells (CSCs) are capable of self-renewal, either by symmetric or asymmetric cell division. They have the exclusive ability to reproduce malignant tumors indefinitely, and to confer resistance in response to radiation or chemotherapy. The ubiquitin modification system plays various roles in physiology and pathology. The key component for the specificity of this system is ubiquitin ligases (E3s). Of these E3s, the majority are RING finger proteins. Many RING finger E3s, such as the Cullin1-Skp1-F-box protein (SCF) E3s, CBL, BRCA1, MDM2 and von Hippel-Lindau tumour suppressor (VHL), are crucial in the regulation of cell-cycle progression and cell differentiation. As a result, many RING finger E3s are implicated in the positive and negative regulation of CSC maintenance. This review summarizes current knowledge in this research field.


A community-based participatory study investigating the epidemiology and effects of rabies to livestock owners in rural Ethiopia.
A participatory study was carried out in the Oromia region of Ethiopia to ascertain the principal epidemiological features of rabies and its impact on livestock owners. Due to the variation in topography (and therefore livestock and human populations within the study area) villages from both high (>1500 m) and lowland areas were included. Local development agents who had no knowledge of the study's purpose recruited a total of one hundred and ninety six participants from eleven lowland and ten highland villages. A facilitator trained in animal health and participatory techniques conducted the interviews with groups of up to eleven participants. Methods used included ranking, scoring, proportion piling, seasonality calendars and open discussions to investigate a set of questions pre determined from a pilot study. The relative importance of rabies to other zoonoses, temporal distributions of the disease, the species affected, current methods of control within affected species and consequences of their loss were all explored. Data was compared between high and lowland areas and previously published studies. The study found that rabies was considered the zoonosis of greatest risk to public health in both areas. It reportedly occurred with higher frequency in highland areas and subsequently affected more livestock in these parts. Two distinct temporal patterns within the areas were described and participants provided reasons of biological plausibility for the occurrence. Livestock were found to contribute as a higher proportion of all species affected than previously shown in published material. This is likely to be due to the low level of reporting of affected animals to the available veterinary services, from where comparative data originated. The death of infected livestock species was found to have numerous social and economic implications and the ramifications of this are made greater by the perception that the highest incidence of clinical disease being in areas of greatest livestock density. The underestimation of the burden of disease by central bodies is likely to influence the economic rationale behind effective rabies control in the future.


Recent trends in racial and regional disparities in cervical cancer incidence and mortality in United States.
Although black women experienced greater cervical cancer incidence and mortality rate reduction in recent years, they continue to have higher incidence rates than whites. Great variations also exist among geographic regions of the US, with the South having both the highest incidence and mortality rates compared to other regions. The present study explores the question of whether living in the South is associated with greater racial disparity in cervical cancer incidence and mortality by examining race- and region-specific rates and the trend between 2000 and 2012. The Surveillance, Epidemiology, and End Results (SEER) 18 Program data was used. Cervical cancer incidence and mortality rates, annual percent changes, and disparity ratios were calculated using SEER*Stat software and Joinpoint regression for four groups: US14-Non-Hispanic White (NHW), US14-Non-Hispanic Black (NHB), South-NHW, and South-NHB, where South included 4 registries from Georgia and Louisiana and US14 were 14 US registries except the four South registries. The average age-adjusted cervical cancer incidence rate was the highest among South-NHBs (11.1) and mortality rate was the highest among US14-NHBs (5.4). In 2012, the degree of racial disparities between South-NHBs and South-NHWs was greater in terms of mortality rates (NHB:NHW = 1.80:1.35) than incidence rates (NHB:NHW = 1.45:1.15). While mortality disparity ratios decreased from 2000-2012 for US14-NHB (APC: -1.9(-2.3,-1.4), mortality disparity ratios for South-NHWs (although lower than NHBs) increased compared to US14-NHW. Incidence rates for NHBs continued to increase with increasing age, whereas rates for NHWs decreased after age 40. Mortality rates for NHBs dramatically increased at age 65 compared to a relatively stable trend for NHWs. The increasing racial disparity with increasing age in terms of cervical cancer incidence rates became more pronounced when corrected for hysterectomy prevalence. Black race and South region were associated with higher cervical cancer incidence and mortality. Cervical cancer rates uncorrected for hysterectomy may underestimate regional and racial disparities. Increasing incidence rates for older NHBs compared to NHWs warrant further research to determine whether screening should continue for NHBs over age 65.


Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation.
AT100 is a monoclonal antibody highly specific for phosphorylated Tau in Alzheimer paired helical filaments. Here we show that the epitope is generated by a complex sequence of sequential phosphorylation, first of Ser199, Ser202 and Thr205 (around the epitope of antibody AT8), next of Thr212 by glycogen synthase kinase (GSK)-3beta (a proline-directed kinase), then of Ser214 by protein kinase A (PKA). Conversely, if Ser214 is phosphorylated first it protects Thr212 and the Ser-Pro motifs around the AT8 site against phosphorylation, and the AT100 epitope is not formed. The generation of the AT100 epitope requires a conformation of tau induced by polyanions such as heparin, RNA or poly(Glu), conditions which also favor the formation of paired helical filaments. The Alzheimer-like phosphorylation can be induced by brain extracts. In the extract, the kinases responsible for generating the AT100 epitope are GSK-3beta and PKA, which can be inhibited by their specific inhibitors LiCl and RII, respectively. A cellular model displaying the reaction with AT100 is presented by Sf9 insect cells transfected with Tau. Knowledge of the events and kinases generating the AT100 epitope in cells might allow us to study the degeneration of the cytoskeleton in Alzheimer's disease.


The acceptability of insecticide treated mosquito nets among community members in Zimbabwe.
To assess the acceptability of insecticide treated mosquito nets (ITNs) among community members in Zimbabwe for the implementation of effective malaria intervention using ITNs. A cross sectional study and longitudinal study were carried out using questionnaires, which were administered by health workers from rural health centres. Communities in rural areas from seven districts namely Bulilimamangwe, Chipinge, Gokwe, Hurungwe, Lupane, Mount Darwin and Uzumba Maramba Pfungwe (UMP) in Zimbabwe. 1,576 community members who bought ITNs in the project areas. Acceptance of ITNs and price, reasons for wanting or not wanting nets; ITNs usage and washing pattern among respondents. More than 90% of people said they bought the nets from the project in order to avoid mosquito bites and to prevent malaria. Quite a number of respondents (69%) gave the answer that they bought mosquito nets from the project because they were cheaper (Z$130 to Z$390) than the market price (Z$1,000) and more than half (58.3%) claimed that they could not afford to buy mosquito nets at the market price. The price was accepted by the majority as cheap or very cheap in Gokwe, Hurungwe, Mount Darwin, and UMP (92%, 82%, 98% and 90%, respectively). Other responses given for having bought nets wereat health staff's recommendation (71.3%), and they were suffering from malaria (40.9%). The reasons for not having bought mosquito nets were that they had not suffered from malaria (55.5%), that they did not like to use a mosquito net (31.1%), did not know the efficacy of the net (21.6%), or there were not many mosquitoes at home (28.9%). The percentage of ITN use was very high (90 to 100%) amongst those who bought nets. The percentage of children under five years and pregnant women who were ITN users ranged from six to 24% to 2.8 to 9.7%, respectively. Percentage of "others" which means those above five years and not pregnant was more than 70% in all the districts. The washing pattern of ITNs in Chipinge showed that most of the mosquito nets (74.5%) were washed every three to five months. Acceptability of ITNs was very high based on reported utilisation of ITNs. It is recommended that rural communities should be sensitised on the importance of treated nets for malaria prevention, and advised to purchase mosquito nets whenever cash is readily available in each community.


Gold-supported two-dimensional cobalt oxyhydroxide (CoOOH) and multilayer cobalt oxide islands.
In the present study, we investigate the facile conversion of Co-O bilayer islands on a Au(111) surface into preferentially O-Co-O trilayers in an oxygen atmosphere and O-Co-O-Co-O multilayers at elevated temperature. We characterize and compare the island morphologies with scanning tunneling microscopy, X-ray photoemission spectroscopy (XPS) and valence band spectroscopy, and show that the cobalt oxidation state changes from Co2+ in bilayers to purely Co3+ in trilayers and a mixture of Co2+ and Co3+ in the multilayer morphology. In contrast to bilayers and multilayers, the trilayer structure appears to grow pseudomorphic with the Au(111) substrate, and in addition we reveal the presence of a hydroxyl overlayer on this island type as evidenced by the appearance of a superstructure in STM correlated with the fingerprints of OH species in XPS and valence band spectroscopy. The obtained layered morphology consisting of hydroxylated trilayer islands is identical to an exfoliated sheet of the β-CoOOH which is proposed to be the active phase of the cobalt oxide oxygen evolution reaction catalyst present in the electrochemical environment, and we note that this synthesized structure thus could serve as a valuable model catalyst.


Versatile single-molecule multi-color excitation and detection fluorescence setup for studying biomolecular dynamics.
Single-molecule fluorescence imaging is at the forefront of tools applied to study biomolecular dynamics both in vitro and in vivo. The ability of the single-molecule fluorescence microscope to conduct simultaneous multi-color excitation and detection is a key experimental feature that is under continuous development. In this paper, we describe in detail the design and the construction of a sophisticated and versatile multi-color excitation and emission fluorescence instrument for studying biomolecular dynamics at the single-molecule level. The setup is novel, economical and compact, where two inverted microscopes share a laser combiner module with six individual laser sources that extend from 400 to 640 nm. Nonetheless, each microscope can independently and in a flexible manner select the combinations, sequences, and intensities of the excitation wavelengths. This high flexibility is achieved by the replacement of conventional mechanical shutters with acousto-optic tunable filter (AOTF). The use of AOTF provides major advancement by controlling the intensities, duration, and selection of up to eight different wavelengths with microsecond alternation time in a transparent and easy manner for the end user. To our knowledge this is the first time AOTF is applied to wide-field total internal reflection fluorescence (TIRF) microscopy even though it has been commonly used in multi-wavelength confocal microscopy. The laser outputs from the combiner module are coupled to the microscopes by two sets of four single-mode optic fibers in order to allow for the optimization of the TIRF angle for each wavelength independently. The emission is split into two or four spectral channels to allow for the simultaneous detection of up to four different fluorophores of wide selection and using many possible excitation and photoactivation schemes. We demonstrate the performance of this new setup by conducting two-color alternating excitation single-molecule fluorescence resonance energy transfer (FRET) and a technically challenging four-color FRET experiments on doubly labeled duplex DNA and quadruple-labeled Holliday junction, respectively.


Clinical indicators associated with HIV acquisition in the United States Air Force.
Mandatory HIV screening of United States Air Force (USAF) personnel every two years effectively identifies incident cases, however testing frequency limits the ability to detect early HIV infection. Identifying clinical indicators of HIV in the USAF population is necessary to develop a supplemental provider-based targeted testing strategy. We conducted a matched case-control study of male active duty USAF personnel with a new HIV diagnosis (n = 452) between 1996 and 2011 matched to five randomly selected controls (n = 2176). The relationship between clinical diagnoses, determined by ICD-9 codes, and HIV infection was assessed using conditional logistic regression. In unadjusted analyses of ICD-9 codes ever and within the last two years before HIV diagnosis, the conditional odds of HIV infection were greater in those with clinical signs and symptoms of HIV (cOR 5.05, 95% CI 4.00-6.39), mental health diagnoses (cOR 2.61, 95% CI 1.86-3.67), and STI diagnoses (cOR 2.33, 95% CI 1.50-3.60). Compared to those with ≤10 medical encounters in the two years prior to HIV diagnosis, individuals with 11-35 medical encounters (cOR 2.19, 95% CI 1.73-2.79) and >35 medical encounters (cOR 4.15, 95% CI 2.69-6.39) had a higher odds of HIV acquisition. In multivariate analyses, clinical signs and symptoms of HIV within the last two years of HIV diagnosis (cOR 4.10, 95% CI 3.22-5.22) and ever having a mental health diagnosis (cOR 1.97, 95% CI 1.44-2.70) remained significant (p < .01). Clinical encounters, particularly those featuring clinical signs and symptoms of HIV or a history of mental health complaints, provide an opportunity for targeted testing as a supplement to mandated testing at two-year intervals. Provider education to increase HIV testing in persons at risk would enhance early HIV diagnosis and potentially reduce forward transmission in the USAF population.


[Prescribed drug use for bipolar disorder type I and II in clinical practice].
Prescribed drug use for bipolar disorder type I and II in clinical practice Practice guidelines based on available evidence and clinical consensus are available for the treatment of bipolar disorder. We surveyed to which extent those guidelines are implemented in clinical practice in Sweden. We analysed pharmacological treatment in patients with bipolar disorder in 2015 using the national quality register for bipolar disorder (BipoläR). We compared bipolar disorder type I (BDI) with type bipolar disorder type II (BDII). The vast majority of patients were prescribed a mood stabilizer either as monotherapy or as a part of combination therapy (BDI 87%, BDII 83%, p<0.001). Whereas lithium was the most common mood stabilizer in type I (BDI 65%, BDII 40%, p<0.001), lamotrigine was the most common mood stabilizer in type II (BDI 18%, BDII 42%, p<0.001). Antidepressants were less common in BDI than BDII (35% vs. 53%, p<0.001). Antipsychotic drugs (first or second generation) were more frequently used in BDI than BDII (49% vs 35%, p<0.001). Central stimulants were rarely used (BDI 3.1%, BDII 6.6%, p<0.001). Combining a mood stabilizer with an antipsychotic drug was more common in BDI than BDII (27% vs. 12%, p<0.001), whereas combining a mood stabilizer with an antidepressant was less common in BDI than BDII (16% vs 28%, p<0.001). We conclude that most patients are prescribed mood stabilizers and that the differences between BDI and BDII are rational given the differences in clinical manifestations. The use of antidepressants is surprisingly high given the long-standing debate about the risk and effectiveness of this class in bipolar disorder.


CRISPR/Cas9 deletions in a conserved exon of Distal-less generates gains and losses in a recently acquired morphological novelty in flies.
Distal-less has been repeatedly co-opted for the development of many novel traits. Here, we document its curious role in the development of a novel abdominal appendage ("sternite brushes") in sepsid flies. CRISPR/Cas9 deletions in the homeodomain result in losses of sternite brushes, demonstrating that Distal-less is necessary for their development. However, deletions in the upstream coding exon (Exon 2) produce losses or gains of brushes. A dissection of Exon 2 reveals that the likely mechanism for gains involves a deletion in an exon-splicing enhancer site that leads to exon skipping. Such contradictory phenotypes are also observed in butterflies, suggesting that mutations in the conserved upstream regions have the potential to generate phenotypic variability in insects that diverged 300 million years ago. Our results demonstrate the importance of Distal-less for the development of a novel abdominal appendage in insects and highlight how site-specific mutations in the same exon can produce contradictory phenotypes.


Effects of anthelmintic treatment and feed supplementation on parasite infections and morbidity parameters in Cambodian cattle.
Helminth infections are the cause of morbidity in Cambodian cattle but other factors such as nutritional deficiencies and concurrent diseases may enhance the effects of parasites. The present study aimed to investigate the impact of anthelmintic treatment, feed supplementation, or both on gastrointestinal strongyle (GIS) and trematode infections as well as on morbidity parameters in Cambodian village cattle. At the beginning of the dry season, cattle populations in six villages were randomly assigned to a group: (A) receiving anthelmintic treatment (ivermectin+clorsulon) at week 0; (P) feed pellet supplementation during week 0-13 or both (AP). On five visits (week 0-29), faecal and blood samples were obtained for parasitological examination and haematocrit determination, respectively. Body condition (BCS), hind quarter fouling (HQFS), diarrhoea (DS), and conjunctiva colour (FAMACHA©) were scored and heart girth circumference was determined. To investigate the impact of treatment over time (week 0-29), a mixed model was used with treatment, time, and their interaction as fixed effects, and animal and village as random factors. At baseline, the proportion of GIS positive animals was high (67.9%), whereas trematode infections were low (Paramphistomum: 8.8%; Fasciola: 2.6%). Very thin to emaciated cattle (BCS 1-2) were more prevalent (11.4%) and FAMACHA© scores of ≤3 or below (65.8%) less prevalent than in an earlier study in the region. A Time ⨯ Treatment interaction was present for faecal egg counts (FEC) of GIS, GIS prevalence (both p<0.0001), PCV (p=0.0034), DS (p=0.0086) and HQFS (p=0.0241). For GIS FEC, treatment groups differed at a specific time point, with levels of treatment group P being higher than in A at week 6 (p=0.0054). For Paramphistomum prevalence as well as FAMACHA© scoring, heart girth and BCS, the interaction between treatment and time was not significant, yet, time in itself had a significant impact on all (p<0.0001). The beneficial effects of protein supplementation were unclear from the current study.


Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
This article discusses the prevention of venous thromboembolism (VTE) and is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggestions imply that individual patient values may lead to different choices (for a full discussion of the grading, see the "Grades of Recommendation" chapter by Guyatt et al). Among the key recommendations in this chapter are the following: we recommend that every hospital develop a formal strategy that addresses the prevention of VTE (Grade 1A). We recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A), and we recommend that mechanical methods of thromboprophylaxis be used primarily for patients at high bleeding risk (Grade 1A) or possibly as an adjunct to anticoagulant thromboprophylaxis (Grade 2A). For patients undergoing major general surgery, we recommend thromboprophylaxis with a low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH), or fondaparinux (each Grade 1A). We recommend routine thromboprophylaxis for all patients undergoing major gynecologic surgery or major, open urologic procedures (Grade 1A for both groups), with LMWH, LDUH, fondaparinux, or intermittent pneumatic compression (IPC). For patients undergoing elective hip or knee arthroplasty, we recommend one of the following three anticoagulant agents: LMWH, fondaparinux, or a vitamin K antagonist (VKA); international normalized ratio (INR) target, 2.5; range, 2.0 to 3.0 (each Grade 1A). For patients undergoing hip fracture surgery (HFS), we recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1B), a VKA (target INR, 2.5; range, 2.0 to 3.0) [Grade 1B], or LDUH (Grade 1B). We recommend that patients undergoing hip or knee arthroplasty or HFS receive thromboprophylaxis for a minimum of 10 days (Grade 1A); for hip arthroplasty and HFS, we recommend continuing thromboprophylaxis > 10 days and up to 35 days (Grade 1A). We recommend that all major trauma and all spinal cord injury (SCI) patients receive thromboprophylaxis (Grade 1A). In patients admitted to hospital with an acute medical illness, we recommend thromboprophylaxis with LMWH, LDUH, or fondaparinux (each Grade 1A). We recommend that, on admission to the ICU, all patients be assessed for their risk of VTE, and that most receive thromboprophylaxis (Grade 1A).


Topological data analysis of collective and individual epithelial cells using persistent homology of loops.
Interacting, self-propelled particles such as epithelial cells can dynamically self-organize into complex multicellular patterns, which are challenging to classify without a priori information. Classically, different phases and phase transitions have been described based on local ordering, which may not capture structural features at larger length scales. Instead, topological data analysis (TDA) determines the stability of spatial connectivity at varying length scales (i.e. persistent homology), and can compare different particle configurations based on the "cost" of reorganizing one configuration into another. Here, we demonstrate a topology-based machine learning approach for unsupervised profiling of individual and collective phases based on large-scale loops. We show that these topological loops (i.e. dimension 1 homology) are robust to variations in particle number and density, particularly in comparison to connected components (i.e. dimension 0 homology). We use TDA to map out phase diagrams for simulated particles with varying adhesion and propulsion, at constant population size as well as when proliferation is permitted. Next, we use this approach to profile our recent experiments on the clustering of epithelial cells in varying growth factor conditions, which are compared to our simulations. Finally, we characterize the robustness of this approach at varying length scales, with sparse sampling, and over time. Overall, we envision TDA will be broadly applicable as a model-agnostic approach to analyze active systems with varying population size, from cytoskeletal motors to motile cells to flocking or swarming animals.


[Fast and spectacular clinical response to plasmapheresis in a paediatric case of anti-NMDA encephalitis].
Autoimmune encephalitis against N-methyl-D-aspartate (NMDA) receptors is being diagnosed more and more frequently in the paediatric age. It should be suspected in children with psychiatric symptoms, encephalopathy, abnormal movements or epileptic seizures. Paraneoplastic cases are less frequent than in adults. We report the case of a boy, 2.5 years of age, with subacute encephalopathic signs and symptoms and epileptic seizures followed by behaviour disorders, neurological regression, dyskinesias and insomnia. Results of a cerebrospinal fluid study were normal, the magnetic resonance scan of the head revealed a focal periventricular lesion and diffuse leptomeningeal uptake; moreover, the serial electroencephalograms showed high-amplitude delta activity interspersed with generalised intercritical epileptiform activity. The patient was given empirical treatment with high doses of corticoids and intravenous immunoglobulins with no response. After showing up positive for antibodies against the NMDA receptor, plasmapheresis was begun, which led to his swift and spectacular recovery. After more than 18 months' follow-up, his sequelae are limited to mild behavioural and language alterations. He has had no relapses and has not needed any kind of maintenance treatment. Anti-NMDA encephalitis is a treatable disorder and, sometimes, the first evidence of an underlying neoplasia, which makes its early recognition and treatment essential. Treatment of the non-paraneoplastic forms are based on immunotherapy: glucocorticoids, intravenous immunoglobulins, plasmapheresis and immunosuppressants. Plasmapheresis can bring about a fast, spectacular improvement.


The Feasibility of Health Trainer Improved Patient Self-Management in Patients with Low Health Literacy and Poorly Controlled Diabetes: A Pilot Randomised Controlled Trial.
Type 2 diabetes mellitus is most prevalent in deprived communities and patients with low health literacy have worse glycaemic control and higher rates of diabetic complications. However, recruitment from this patient population into intervention trials is highly challenging. We conducted a study to explore the feasibility of recruitment and to assess the effect of a lay health trainer intervention, in patients with low health literacy and poorly controlled diabetes from a socioeconomically disadvantaged population, compared with usual care. Methods. A pilot RCT comparing the LHT intervention with usual care. Patients with HbA1c > 7.5 (58 mmol/mol) were recruited. Baseline and 7-month outcome data were entered directly onto a laptop to reduce patient burden. Results. 76 patients were recruited; 60.5% had low health literacy and 75% were from the most deprived areas of England. Participants in the LHT arm had significantly improved mental health (p = 0.049) and illness perception (p = 0.040). The intervention was associated with lower resource use, better patient self-care management, and better QALY profile at 7-month follow-up. Conclusion. This study describes successful recruitment strategies for hard-to-reach populations. Further research is warranted for this cost-effective, relatively low-cost intervention for a population currently suffering a disproportionate burden of diabetes, to demonstrate its sustained impact on treatment effects, health, and health inequalities.


Feasibility, safety, acceptability, and yield of office-based, screening transnasal esophagoscopy (with video).
Endoscopic screening for esophageal neoplasia can identify patients eligible for early intervention for precancerous lesions. Unsedated transnasal esophagoscopy may provide an efficient and accurate endoscopic assessment with fewer risks and less cost, compared with conventional upper endoscopy. To assess the feasibility, safety, acceptability, and yield of unsedated transnasal esophagoscopy in a primary care population. Multicenter, prospective, cross-sectional study. Two outpatient tertiary-care centers. This study involved a general medical clinic population aged between 40 and 85 years. Unsedated, office-based transnasal esophagoscopy. Procedure yield; completeness of examination; procedure length; adverse events and complications; choking, gagging, pain, or anxiety during the examination; and overall tolerability. A total of 426 participants (mean [± standard deviation] age 55.8 ± 9.5 years; 43% male) enrolled in the study, and 422 (99%) completed the examination. Mean (± standard deviation) examination time was 3.7 ± 1.8 minutes. There were no serious adverse events, and 12 participants (2.8%) reported minor complications. Participants reported minimal choking, gagging, pain, or anxiety. The examination was well-tolerated by most participants. Overall, 38% of participants had an esophageal finding that changed management (34% erosive esophagitis, 4% Barrett's esophagus). Nonrandomized study, tertiary-care centers only, self-selected population with a large proportion reporting esophageal symptoms. Unsedated transnasal esophagoscopy is a feasible, safe, and well-tolerated method to screen for esophageal disease in a primary care population. Endoscopic findings are common in this patient population.


Linking Native and Invader Traits Explains Native Spider Population Responses to Plant Invasion.
Theoretically, the functional traits of native species should determine how natives respond to invader-driven changes. To explore this idea, we simulated a large-scale plant invasion using dead spotted knapweed (Centaurea stoebe) stems to determine if native spiders' web-building behaviors could explain differences in spider population responses to structural changes arising from C. stoebe invasion. After two years, irregular web-spiders were >30 times more abundant and orb weavers were >23 times more abundant on simulated invasion plots compared to controls. Additionally, irregular web-spiders on simulated invasion plots built webs that were 4.4 times larger and 5.0 times more likely to capture prey, leading to >2-fold increases in recruitment. Orb-weavers showed no differences in web size or prey captures between treatments. Web-spider responses to simulated invasion mimicked patterns following natural invasions, confirming that C. stoebe's architecture is likely the primary attribute driving native spider responses to these invasions. Differences in spider responses were attributable to differences in web construction behaviors relative to historic web substrate constraints. Orb-weavers in this system constructed webs between multiple plants, so they were limited by the overall quantity of native substrates but not by the architecture of individual native plant species. Irregular web-spiders built their webs within individual plants and were greatly constrained by the diminutive architecture of native plant substrates, so they were limited both by quantity and quality of native substrates. Evaluating native species traits in the context of invader-driven change can explain invasion outcomes and help to identify factors limiting native populations.


Right ventricular fibrosis is associated with cardiac remodelling after pulmonary valve replacement.
The relationship between right ventricular (RV) fibrosis and right heart reverse remodelling following pulmonary valve replacement (PVR) has not been well studied in adults with repaired tetralogy of Fallot (rTOF). Our aims were to histologically quantify RV fibrosis and to explore the relationship between fibrosis severity and cardiac remodelling post-PVR. Adults with rTOF and pre-PVR cardiovascular (CMR) imaging were consented to procurement of RV muscle during PVR. Samples were stained with picrosirius red to quantify collagen volume fraction. Clinical data at baseline and at last follow-up were reviewed. Adverse cardiovascular outcomes included death, sustained arrhythmia and heart failure. Fifty-three patients (male 58%, 38±11 years) were studied. Those with severe fibrosis (collagen volume fraction >11.0%, n=13) had longer aortic cross-clamp times at initial repair compared with the remainder of the population (50 vs 33 min, p=0.018) and increased RV mass:volume ratio pre-PVR (0.20 vs 0.18 g/mL, p=0.028). Post-PVR, the severe fibrosis group had increased indexed RV end-systolic volume index (RVESVi) (74 vs 66 mL/m2, p=0.044), decreased RVESVi change (Δ29 vs Δ45 mL/m2, p=0.005), increased RV mass (34 vs 25 g/m2, p=0.023) and larger right atrial (RA) area (21 vs 17 cm2, p=0.021). A trend towards increased heart failure events was observed in the severe fibrosis group (15% vs 0%, p=0.057). Severe RV fibrosis was associated with increased RVESVi, RV mass and RA area post-PVR in rTOF. Further study is required to define the impact of fibrosis and persistent right heart enlargement on clinical outcomes.


Nonlinear time series analysis of normal and pathological human walking.
Characterizing locomotor dynamics is essential for understanding the neuromuscular control of locomotion. In particular, quantifying dynamic stability during walking is important for assessing people who have a greater risk of falling. However, traditional biomechanical methods of defining stability have not quantified the resistance of the neuromuscular system to perturbations, suggesting that more precise definitions are required. For the present study, average maximum finite-time Lyapunov exponents were estimated to quantify the local dynamic stability of human walking kinematics. Local scaling exponents, defined as the local slopes of the correlation sum curves, were also calculated to quantify the local scaling structure of each embedded time series. Comparisons were made between overground and motorized treadmill walking in young healthy subjects and between diabetic neuropathic (NP) patients and healthy controls (CO) during overground walking. A modification of the method of surrogate data was developed to examine the stochastic nature of the fluctuations overlying the nominally periodic patterns in these data sets. Results demonstrated that having subjects walk on a motorized treadmill artificially stabilized their natural locomotor kinematics by small but statistically significant amounts. Furthermore, a paradox previously present in the biomechanical literature that resulted from mistakenly equating variability with dynamic stability was resolved. By slowing their self-selected walking speeds, NP patients adopted more locally stable gait patterns, even though they simultaneously exhibited greater kinematic variability than CO subjects. Additionally, the loss of peripheral sensation in NP patients was associated with statistically significant differences in the local scaling structure of their walking kinematics at those length scales where it was anticipated that sensory feedback would play the greatest role. Lastly, stride-to-stride fluctuations in the walking patterns of all three subject groups were clearly distinguishable from linearly autocorrelated Gaussian noise. As a collateral benefit of the methodological approach taken in this study, some of the first steps at characterizing the underlying structure of human locomotor dynamics have been taken. Implications for understanding the neuromuscular control of locomotion are discussed. (c) 2000 American Institute of Physics.