Ovarian cancer treatment in mutation carriers/BRCAness.
Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5-year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Retrospective studies have shown an improved prognosis, higher response rates to platinum-containing regimens, and longer treatment-free intervals between relapses in patients with BRCA 1 and BRCA 2 (BRCA1/2)-mutated ovarian cancer (BMOC) compared with patients who are not carriers of this mutation. These features of BMOC are attributed to homologous-recombination repair deficiency in the absence of BRCA1/2 function, which results in an impaired ability of tumor cells to repair platinum-induced double-strand breaks, thereby conferring increased chemosensitivity and increased sensitivity to poly(ADP-ribose) polymerase enzyme inhibition and other DNA-damaging chemotherapeutic agents such as pegylated liposomal doxorubicin (PLD). Therefore, the chemotherapeutic approach for patients with BMOC should focus on treatment with platinum-based chemotherapy at first-line and recurrent-disease settings and measures to increase the platinum-free interval following early platinum-resistant relapse by using non-platinum cytotoxic agents, with the aim of reintroducing platinum again at a later date. The role of first-line intraperitoneal platinum-based therapy in the specific context of BMOC also merits further analysis. Other than platinum, alternative DNA-damaging agents (including PLD and trabectedin) also may have a therapeutic role in patients with recurrent BMOC. The approval of olaparib for clinical use in Europe and the United States will also affect chemotherapeutic strategies for these patients. Further work to clarify the precise relationship between BRCA1/2 mutation genotype and clinical phenotype is crucial to delineating the optimal therapeutic choices in the future for patients with BMOC.


Update: ebola virus disease epidemic - West Africa, December 2014.
CDC is assisting ministries of health and working with other organizations to end the ongoing epidemic of Ebola virus disease (Ebola) in West Africa. The updated data in this report were compiled from situation reports from the Guinea Interministerial Committee for Response Against the Ebola Virus, the World Health Organization, the Liberia Ministry of Health and Social Welfare, and the Sierra Leone Ministry of Health and Sanitation. Total case counts include all suspected, probable, and confirmed cases, which are defined similarly by each country. These data reflect reported cases, which make up an unknown proportion of all cases, and reporting delays that vary from country to country.


Identification, classification, and signal amplification capabilities of high-turnover gas binding hosts in ultra-sensitive NMR.
Nuclear Magnetic Resonance (NMR) can be a powerful tool for investigating exchange kinetics of host-guest interactions in solution. Beyond conventional direct NMR detection, radiofrequency (RF) saturation transfer can be used to enhance the study of such chemical exchange or to enable signal amplification from a dilute host. However, systems that are both dilute and labile (fast dissociation/re-association) impose specific challenges to direct as well as saturation transfer detection. Here we investigate host-guest systems under previously inaccessible conditions using saturation transfer techniques in combination with hyperpolarized nuclei and quantitative evaluation under different RF exposure. We further use that information to illustrate the consequences for signal amplification capabilities and correct interpretation of observed signal contrast from comparative exchange data of different types of hosts. In particular, we compare binding of xenon (Xe) to cucurbit[6]uril (CB6) with binding to cryptophane-A monoacid (CrA) in water as two different model systems. The Xe complexation with CB6 is extremely difficult to access by conventional NMR due to its low water solubility. We successfully quantified the exchange kinetics of this system and found that the absence of Xe signals related to encapsulated Xe in conventional hyperpolarized 129Xe NMR is due to line broadening and not due to low binding. By introducing a measure for the gas turnover during constant association-dissociation, we demonstrate that the signal amplification from a dilute pool of CB6 can turn this host into a very powerful contrast agent for Xe MRI applications (100-fold more efficient than cryptophane). However, labile systems only provide improved signal amplification for suitable saturation conditions and otherwise become disadvantageous. The method is applicable to many hosts where Xe is a suitable spy nucleus to probe for non-covalent interactions and should foster reinvestigation of several systems to delineate true absence of interaction from labile complex formation.


Additional genomic aberrations identified by single nucleotide polymorphism array-based karyotyping in an acute myeloid leukemia case with isolated del(20q) abnormality.
Prognosis is known to be better in cases with isolated chromosomal abnormalities than in those with complex karyotypes. Accordingly, del(20q) as an isolated abnormality must be distinguished from cases in which it is associated with other chromosomal rearrangements for a better stratification of prognosis. We report a case of an isolated del(20q) abnormality with additional genomic aberrations identified using whole-genome single nucleotide polymorphism array (SNP-A)-based karyotyping. A 39-yr-old man was diagnosed with AML without maturation. Metaphase cytogenetic analysis (MC) revealed del(20)(q11.2) as the isolated abnormality in 100% of metaphase cells analyzed, and FISH analysis using D20S108 confirmed the 20q deletion in 99% of interphase cells. Using FISH, other rearrangements such as BCR/ABL1, RUNX1/RUNX1T1, PML/RARA, CBFB/MYH11, and MLL were found to be negative. SNP-A identified an additional copy neutral loss of heterozygosity (CN-LOH) in the 11q13.1-q25 region. Furthermore, SNP-A allowed for a more precise definition of the breakpoints of the 20q deletion (20q11.22-q13.31). Unexpectedly, the terminal regions showed gain on chromosome 20q. The patient did not achieve complete remission; 8 months later, he died from complications of leukemic cell infiltrations into the central nervous system. This study suggests that a presumably isolated chromosomal abnormality by MC may have additional genomic aberrations, including CN-LOH, which could be associated with a poor prognosis. SNP-A-based karyotyping may be helpful for distinguishing true isolated cases from cases in combination with additional genomic aberrations not detected by MC.


Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes).
African black-footed cats (Felis nigripes) are endangered wild felids. One male and full-sibling female African black-footed cat developed vision deficits and mydriasis as early as 3 months of age. The diagnosis of early-onset progressive retinal atrophy (PRA) was supported by reduced direct and consensual pupillary light reflexes, phenotypic presence of retinal degeneration, and a non-recordable electroretinogram with negligible amplitudes in both eyes. Whole genome sequencing, conducted on two unaffected parents and one affected offspring was compared to a variant database from 51 domestic cats and a Pallas cat, revealed 50 candidate variants that segregated concordantly with the PRA phenotype. Testing in additional affected cats confirmed that cats homozygous for a 2 base pair (bp) deletion within IQ calmodulin-binding motif-containing protein-1 (IQCB1), the gene that encodes for nephrocystin-5 (NPHP5), had vision loss. The variant segregated concordantly in other related individuals within the pedigree supporting the identification of a recessively inherited early-onset feline PRA. Analysis of the black-footed cat studbook suggests additional captive cats are at risk. Genetic testing for IQCB1 and avoidance of matings between carriers should be added to the species survival plan for captive management.


Space geodetic observations of nazca-south america convergence across the central andes
Space geodetic data recorded rates and directions of motion across the convergent boundary zone between the oceanic Nazca and continental South American plates in Peru and Bolivia. Roughly half of the overall convergence, about 30 to 40 millimeters per year, accumulated on the locked plate interface and can be released in future earthquakes. About 10 to 15 millimeters per year of crustal shortening occurred inland at the sub-Andean foreland fold and thrust belt, indicating that the Andes are continuing to build. Little (5 to 10 millimeters per year) along-trench motion of coastal forearc slivers was observed, despite the oblique convergence.


Characterization of functional and structural integrity in experimental focal epilepsy: reduced network efficiency coincides with white matter changes.
Although focal epilepsies are increasingly recognized to affect multiple and remote neural systems, the underlying spatiotemporal pattern and the relationships between recurrent spontaneous seizures, global functional connectivity, and structural integrity remain largely unknown. Here we utilized serial resting-state functional MRI, graph-theoretical analysis of complex brain networks and diffusion tensor imaging to characterize the evolution of global network topology, functional connectivity and structural changes in the interictal brain in relation to focal epilepsy in a rat model. Epileptic networks exhibited a more regular functional topology than controls, indicated by a significant increase in shortest path length and clustering coefficient. Interhemispheric functional connectivity in epileptic brains decreased, while intrahemispheric functional connectivity increased. Widespread reductions of fractional anisotropy were found in white matter regions not restricted to the vicinity of the epileptic focus, including the corpus callosum. Our longitudinal study on the pathogenesis of network dynamics in epileptic brains reveals that, despite the locality of the epileptogenic area, epileptic brains differ in their global network topology, connectivity and structural integrity from healthy brains.


Inorganic carbon fixation by chemosynthetic ectosymbionts and nutritional transfers to the hydrothermal vent host-shrimp Rimicaris exoculata.
The shrimp Rimicaris exoculata dominates several hydrothermal vent ecosystems of the Mid-Atlantic Ridge and is thought to be a primary consumer harbouring a chemoautotrophic bacterial community in its gill chamber. The aim of the present study was to test current hypotheses concerning the epibiont's chemoautotrophy, and the mutualistic character of this association. In-vivo experiments were carried out in a pressurised aquarium with isotope-labelled inorganic carbon (NaH(13)CO(3) and NaH(14)CO(3)) in the presence of two different electron donors (Na(2)S(2)O(3) and Fe(2+)) and with radiolabelled organic compounds ((14)C-acetate and (3)H-lysine) chosen as potential bacterial substrates and/or metabolic by-products in experiments mimicking transfer of small biomolecules from epibionts to host. The bacterial epibionts were found to assimilate inorganic carbon by chemoautotrophy, but many of them (thick filaments of epsilonproteobacteria) appeared versatile and able to switch between electron donors, including organic compounds (heterotrophic acetate and lysine uptake). At least some of them (thin filamentous gammaproteobacteria) also seem capable of internal energy storage that could supply chemosynthetic metabolism for hours under conditions of electron donor deprivation. As direct nutritional transfer from bacteria to host was detected, the association appears as true mutualism. Import of soluble bacterial products occurs by permeation across the gill chamber integument, rather than via the digestive tract. This first demonstration of such capabilities in a decapod crustacean supports the previously discarded hypothesis of transtegumental absorption of dissolved organic matter or carbon as a common nutritional pathway.


Early Maternal Employment and Children's Academic and Behavioral Skills in Australia and the United Kingdom.
This study assessed the links between early maternal employment and children's later academic and behavioral skills in Australia and the United Kingdom. Using representative samples of children born in each country from 2000 to 2004 (Australia N = 5,093, U.K. N = 18,497), OLS regression models weighted with propensity scores assessed links between maternal employment in the 2 years after childbearing and children's skills in first grade. There were neutral associations between maternal employment and children's first-grade skills in both countries. However, there was a slight indication that more time away from parenting was negatively linked to children's behavioral functioning in Australia and employment begun between 9 and 24 months was positively linked to cognitive skills for U.K. children of low-wage mothers.


Characteristics and frequency of detection of fecal Listeria monocytogenes shed by livestock, wildlife, and humans.
Listeria monocytogenes is a facultative intracellular pathogen that can be carried asymptomatically in various animals and can be shed in feces. We investigated the prevalence and characteristics of L. monocytogenes isolated from livestock, wildlife, and human potential sources of contamination in 2 areas in Ontario, Canada. From February 2003 to November 2005, a total of 268 fecal samples were collected from different animals. Listeria monocytogenes was isolated using selective enrichment, isolation, and confirmation procedures, and 15 samples (6%) yielded to the isolation of 84 confirmed strains. Listeria monocytogenes was isolated from livestock (beef and dairy), wildlife (deer, moose, otter, and raccoon), and human (biosolids and septic) fecal sources. Thirty-two isolates were from serovar 1/2a, 34 from serovar 1/2b, 1 from serovar 3a, and 17 from serovar 4b. Listeria monocytogenes populations were resolved into 13 EcoRI ribotypes, and 18 ApaI and 18 AscI pulsotypes, with Simpson indexes of discrimination of 0.878 and 0.907, respectively. A majority (59%) of L. monocytogenes isolates exhibited potential virulence linked to the production of a functional internalin A, which was supported by higher entry into Caco-2 cells (9.3%) than isolates producing truncated and secreted internalin A (1.3% of entry). Listeria monocytogenes fecal isolates were on average resistant to 6.4 +/- 2.5 antibiotics out of 17 tested, and potentially virulent isolates exhibited an enhanced resistance to kanamycin, gentamicin, streptomycin, and rifampicin. Livestock, wildlife, and human L. monocytogenes fecal communities exhibited overlapping but distinct populations, and some genotypes and phenotypes were similar to those previously described for surface water isolates in the same area.


Correction of error in respiratory resistance measurements made with the flow-interruption technique during mechanical ventilation: evaluation of the puritan bennett 7200 and 840 ventilators.
Calculation of total inspiratory resistance (Rtot) for patients on ventilatory support is typically based on measurement of airflow velocity and airway opening pressure during end-inspiratory occlusion by the inspiratory valve in the ventilator. Systematic error is introduced into Rtot measurements because the inspiratory valve closes over a period of time (not instantaneously, so gas continues to flow into the circuit while the valve is shutting) and because the circuit tubing is a distensible compartment between the occluding valve and the respiratory system. The Rtot-measurement error can be minimized with a rapidly-shutting occlusion valve positioned at the airway opening, or, alternatively, by mathematical correction that accounts for the valve-closure period and circuit tubing characteristics. In a bench study we measured Rtot with the Puritan Bennett 7200 and 840 ventilators (using the inspiratory valves that are built into those ventilators) and compared those measurements to measurements made with a rapidly-shutting valve at the airway opening. We deemed the rapid-occlusion-valve measurements the best available (benchmark) values. We also studied the closure characteristics of the ventilators' inspiratory occlusion valves and created equations for mathematical correction of Rtot values measured with those valves. Compared to the benchmark measurements, the measurements from the Puritan Bennett 7200 averaged 23.2% relative error and 2.6 cm H2O/L/s absolute error. Measurements from the Puritan Bennett 840 averaged 7.3% relative error and 1.0 cm H2O/L/s absolute error. Mathematical correction for the circuit tubing and valve-closure time reduced the average relative and absolute error to 3.0% and 0.4 cm H2O/L/s, respectively, for the Puritan Bennett 7200, and to 4.5% and 0.3 cm H2O/L/s, respectively, for the Puritan Bennett 840. The Puritan Bennett 840 measures Rtot more accurately than the Puritan Bennett 7200. Our equations to mathematically correct Rtot measurements made with the PB7200 and PB840 are useful in settings where very accurate Rtot measurements are necessary.


A robot made of robots: Emergent transport and control of a smarticle ensemble.
Robot locomotion is typically generated by coordinated integration of single-purpose components, like actuators, sensors, body segments, and limbs. We posit that certain future robots could self-propel using systems in which a delineation of components and their interactions is not so clear, becoming robust and flexible entities composed of functional components that are redundant and generic and can interact stochastically. Control of such a collective becomes a challenge because synthesis techniques typically assume known input-output relationships. To discover principles by which such future robots can be built and controlled, we study a model robophysical system: planar ensembles of periodically deforming smart, active particles-smarticles. When enclosed, these individually immotile robots could collectively diffuse via stochastic mechanical interactions. We show experimentally and theoretically that directed drift of such a supersmarticle could be achieved via inactivation of individual smarticles and used this phenomenon to generate endogenous phototaxis. By numerically modeling the relationship between smarticle activity and transport, we elucidated the role of smarticle deactivation on supersmarticle dynamics from little data-a single experimental trial. From this mapping, we demonstrate that the supersmarticle could be exogenously steered anywhere in the plane, expanding supersmarticle capabilities while simultaneously enabling decentralized closed-loop control. We suggest that the smarticle model system may aid discovery of principles by which a class of future "stochastic" robots can rely on collective internal mechanical interactions to perform tasks.


Prognostic impact of moderate or severe mitral regurgitation (MR) irrespective of concomitant comorbidities: a retrospective matched cohort study.
We sought to objectively quantify the independent impact of significant mitral regurgitation (MR) on prognosis in patients with multiple comorbidities and ascertain the extent to which median survival is affected by increasing comorbidities. This was a retrospective matched cohort study using a clinical-echocardiography reporting database linked to a clinical and administrative database in an Australian tertiary hospital. We identified our study cohort (patients with significant MR) and control cohort (without MR) on transthoracic echocardiographies performed between 2005 and 2010. The main outcome measures were mortality and heart failure rehospitalisation. A Cox proportional hazards model was used to adjust for clinical covariates and the 'win ratio' methodology was utilised to estimate the impact of MR on main outcomes. A total of 218 matched patients with and without significant MR were followed-up for 1 year. Significant MR was associated with an adjusted HR for mortality of 1.83 (95% CI 1.28 to 2.62, p<0.001). The win ratio for death and death or heart failure readmission was 0.57 (95% CI 0.40 to 0.78, p=0.0002) and 0.53 (95% CI 0.39 to 0.71, p<0.0001), respectively. Significant MR with left ventricular (LV) systolic dysfunction and age between 75 and 85 years were associated with a substantial reduction in median survival by 2.3 years. Significant MR with LV systolic dysfunction, age beyond 85 and advance comorbidities were associated with a lesser reduction in median survival by 0.2 years. Significant MR in patients with multiple comorbidities leads to increase in death and heart failure rehospitalisation with reduced estimated median survival. However, its impact diminishes with increasing comorbidities.


The effect of plasma transfusion on morbidity and mortality: a systematic review and meta-analysis.
Plasma transfusion is increasingly performed without clear consensus on indications. We systematically reviewed the literature to summarize the available evidence regarding the benefits and harms of plasma transfusion in common clinical settings. We searched electronic databases from inception through August 2009. Eligible studies enrolled adult patients transfused with plasma and compared to a control group. Paired reviewers independently assessed studies for eligibility and extracted quality and outcome data. Thirty-seven studies met eligibility criteria, most of which were observational. In patients undergoing massive transfusion, plasma infusion at high plasma : red blood cell ratios was associated with a significant reduction in the risk of death (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.24-0.60) and multiorgan failure (OR, 0.40; 95% CI, 0.26-0.60). However, the quality of this evidence was very low due to significant unexplained heterogeneity and several other biases. In a single retrospective study, plasma transfusion was associated with reduced mortality in anticoagulated patients with intracranial hemorrhage (OR, 0.29; 95% CI, 0.09-0.98). In patients undergoing surgery without massive transfusion, plasma infusion was associated with a trend toward increased mortality (OR, 1.22; 95% CI, 0.73-2.03). Plasma transfusion was associated with increased risk of developing acute lung injury (OR, 2.92; 95% CI, 1.99-4.29). Very-low-quality evidence suggests that plasma infusion in the setting of massive transfusion for trauma patients may be associated with a reduction in the risk of death and multiorgan failure. A survival benefit was not demonstrated in most other transfusion populations.


A tightly controlled Src-YAP signaling axis determines therapeutic response to dasatinib in renal cell carcinoma.
Over the past decade, therapies targeting the VEGF/VEGFR and mTOR pathways have served as the standard of care for the clinical management of renal cell carcinoma (RCC) patients. Albeit promising, these targeted drugs have attained only modest clinical benefits with limited prolonged progression-free survival. Therefore, alternative reasonable and applicable therapeutic approaches should be introduced to improve the clinical outcome of RCC patients. Methods: FDA approved kinase inhibitors were screened to evaluate their abilities to suppress the proliferation of RCC cells. Then, the downstream effector, therapeutic target and signaling pathway of the selected drug were identified by gene expression array, RNAi, kinase profile and rescue verification. Finally, the in vivo effectiveness of the drug was assessed in cell line-based xenograft models and patient-derived xenograft models. Results: In this study, we discovered that dasatinib is a potent agent that can impair RCC cell viability in vitro and decrease tumor growth in vivo. Mechanistically, we improved the understanding of the precise mechanistic role of YAP as a pivotal effector of dasatinib-induced anti-proliferation through Src-JNK-LIMD1-LATS signaling cascade in RCC cells. Meanwhile, our results indicated that the alteration of p-YAP is closely correlated to the growth inhibition caused by dasatinib in sensitive RCC models. Conclusion: Our findings provide evidence that dasatinib may serve as a powerful drug candidate to treat subgroups of RCC patients with hyper-activated Src-YAP signaling axis, and the alteration of p-YAP could serve as a functional response biomarker of dasatinib in RCC.


Synthetic circuit identifies subpopulations with sustained memory of DNA damage.
Differential responses to stimuli can affect how cells succumb to disease. In yeast, DNA damage can create heterogeneous responses. To delineate how a response contributes to a cell's future behavior, we constructed a transcription-based memory circuit that detects DNA repair to isolate subpopulations with heritable damage responses. Strongly responsive cells show multigenerational effects, including growth defects and iron-associated gene expression. Less-responsive cells exhibit increased mutation frequencies but resume wild-type behavior. These two subpopulations remain distinct for multiple generations, indicating a transmissible memory of damage. Collectively, this work demonstrates the efficacy of using synthetic biology to define how environmental exposure contributes to distinct cell fates.


NADPH: cytochrome P-450 reductase in olfactory epithelium. Relevance to cytochrome P-450-dependent reactions.
The presence of a very active cytochrome P-450-dependent drug-metabolizing system in the olfactory epithelium has been confirmed by using 7-ethoxycoumarin, 7-ethoxyresorufin, hexobarbitone and aniline as substrates, and the reasons for the marked activity of the cytochrome P-450 in this tissue have been investigated. The spectral interaction of hexobarbitone and aniline with hepatic and olfactory microsomes has been examined. By this criterion there was no evidence for marked differences in the spin state of the cytochromes of the two tissues, or for the olfactory epithelium containing a greater amount of cytochrome capable of binding hexobarbitone, a very actively metabolized substrate. Rates of NADPH and NADH: cytochrome c reductase activity were found to be higher in the olfactory epithelium than in the liver, and direct evidence was obtained for a greater amount of the NADPH-dependent flavoprotein in the olfactory microsomes. Investigation of male rats and male and female mice, as well as male hamsters, demonstrated that, in all cases, the cytochrome P-450 levels of the olfactory epithelium were lower than those of the liver, while the 7-ethoxycoumarin de-ethylase and NADPH:cytochrome c reductase activities were higher. A correlation was found between 7-ethoxycoumarin de-ethylase and NADPH:cytochrome c reductase activities for both tissues in all species examined. The ratio of reductase to cytochrome P-450 was found to be considerably higher in the olfactory epithelium (1:2-1:3) than in the liver (1:11-1:15), regardless of the species examined, suggesting that facilitated electron flow may contribute significantly to the cytochrome P-450 catalytic turnover in the olfactory tissue.


Body composition for health and performance: a survey of body composition assessment practice carried out by the Ad Hoc Research Working Group on Body Composition, Health and Performance under the auspices of the IOC Medical Commission.
Successful performers in weight-sensitive sports are characterised by low body mass (BM) and fat content. This often requires chronic energy restriction and acute weight loss practices. To evaluate current use of body composition (BC) assessment methods and identify problems and solutions with current BC approaches. A 40-item survey was developed, including demographic and content questions related to BC assessment. The survey was electronically distributed among international sporting organisations. Frequencies and χ(2) analyses were computed. 216 responses were received, from 33 countries, representing various institutions, sports and competitive levels. Of the sample, 86% of respondents currently assess BC, most frequently using skinfolds (International Society for the Advancement of Kinanthropometry (ISAK): 50%; non-ISAK, conventional: 40%; both: 28%), dual energy X-ray absorptiometry (38%), bioelectrical impedance (29%), air displacement plethysmography (17%) and hydrostatic weighing (10%). Of those using skinfolds, more at the international level used ISAK, whereas conventional approaches were more reported at regional/national level (p=0.006). The sport dietitian/nutritionist (57%) and physiologist/sports scientist (54%) were most frequently the professionals assessing BC, followed by MDs and athletic trainers, with some reporting coaches (5%). 36% of 116 respondents assessed hydration status and more (64%) did so at international than regional/national level (36%, p=0.028). Of 125 participants answering the question of whether they thought that BC assessment raised problems, 69% said 'yes', with most providing ideas for solutions. Results show high use of BC assessment but also a lack of standardisation and widespread perception of problems related to BM and BC in sport. Future work should emphasise standardisation with appropriate training opportunities and more research on BC and performance.


The mechanisms of UV radiation in the development of malignant melanoma.
The sunlight was one of the first agents recognized to be carcinogenic for humans. There is convincing evidence from epidemiologic studies that exposure to solar radiation is the major cause of cutaneous melanoma in light-pigmented populations and plays a role in the increasing incidence of this malignancy. The molecular mechanisms by which UV radiation exerts its varied effects are not completely understood, however, it is considered that UVA and UVB are equally critical players in melanoma formation. Whereas UVA can indirectly damage DNA through the formation of reactive oxygen radicals, UVB can directly damage DNA causing the apoptosis of keratinocytes by forming the sunburn cells. Besides action through mutations in critical regulatory genes, UV radiation may promote cancer through indirect mechanisms, e.g. immunosuppression and dysregulation of growth factors. The carcinogenic process probably involves multiple sequential steps, some, but not all of which involve alterations in DNA structure.


Why Do You Ride?: A Characterization of Mountain Bikers, Their Engagement Methods, and Perceived Links to Mental Health and Well-Being.
Mountain biking is an increasingly popular outdoor activity on the extreme sport continuum. Extreme and high-risk sports have been investigated using a variety of motivational theories with sensation seeking a dominant theme; however, behavioral and motivational homogeneity within these types of populations should not be assumed. Recent studies have highlighted the therapeutic potential of extreme sports and similar outdoor activities. The aim of this study was to describe the characteristics of mountain biking participants, their engagement methods, and perceived benefits to mental health and well-being. This was a cross-sectional survey and participants were recruited via social media. An online questionnaire specific to the domain of mountain biking was developed. Analysis of the full sample (n = 1,484) and of three independent paired sub-samples was conducted using SPSS. The sub-samples compared the results of males and females; younger and older riders; and those who have recently engaged in downhill mountain biking and those who have not. The results have succeeded in identifying some disparities in mountain biker characteristics and engagement methods. The results suggest that some riders found pleasure in higher risk engagement. The study proposes various explanations for the disproportion of women in mountain biking. Irrespective of the confounding factors related to rider characteristics or engagement methods, mountain bikers reported copious benefits to mental health and well-being related to their engagement. There was a high reported usage of mountain biking as a coping strategy. As such, this study provides insights that could inform the development of outdoor activities as interventions for mental health.


Non-noble metal plasmonic photocatalysis in semimetal bismuth films for photocatalytic NO oxidation.
Recently, non-noble metals with plasmonic properties have attracted great attention due to their potential applications in photocatalytic solar-energy conversion. However, in contrast to the well-studied plasmonic noble metals (mainly Au and Ag), which have distinct absorption peaks, the understanding of light absorption and the photocatalytic reaction mechanism of non-noble metals is far less. In this study, semimetal bismuth films are deposited on fluorine-doped tin oxide substrates by a dc magnetron sputtering method. Both theoretical calculation and UV-vis absorption spectra confirm that the field enhancement and location of plasmonic resonance peaks are strongly correlated with the size of Bi particles. Through tuning the sputtering power, for the first time, four distinct absorption peaks are observed over isolated Bi particles. Moreover, it is found that the energy barrier for the conversion of NO into NO2 over Bi is even lower than that with Au nanoclusters. Thus, Bi films are highly active for photocatalytic oxidation of NO. Moreover, the low NO2 desorption energy over Bi indicates that Bi films can be the main active sites during the reaction process and that they possess good stability.


Microbiological effectiveness of locally produced ceramic filters for drinking water treatment in Cambodia.
Low-cost options for the treatment of drinking water at the household level are being explored by the Cambodian government and non-governmental organizations (NGOs) working in Cambodia, where many lack access to improved drinking water sources and diarrhoeal diseases are the most prevalent cause of death in children under 5 years of age. The ceramic water purifier (CWP), a locally produced, low-cost ceramic filter, is now being implemented by several NGOs, and an estimated 100,000+households in the country now use them for drinking water treatment. Two candidate filters were tested for the reduction of bacterial and viral surrogates for waterborne pathogens using representative Cambodian drinking water sources (rainwater and surface water) spiked with Escherichia coli and bacteriophage MS2. Results indicate that filters were capable of reducing key microbes in the laboratory with mean reductions of E. coli of approximately 99% and mean reduction of bacteriophages of 90-99% over >600 litres throughput. Increased effectiveness was not observed in filters with an AgNO3 amendment. At under US$10 per filter, locally produced ceramic filters may be a promising option for drinking water treatment and safe storage at the household level.


Clinical Decision-Making in the Treatment of Schizophrenia: Focus on Long-Acting Injectable Antipsychotics.
The purpose of this study was to identify clinician characteristics associated with higher prescription rates of long-acting injectable (LAI) antipsychotics, as well as the sources that influence medical decision-making regarding the treatment of schizophrenia. We surveyed 202 psychiatrists during six regional French conferences (Bordeaux, Lyon, Marseille, Nice, Paris, and Strasbourg). Data on the characteristics of practice, prescription rates of antipsychotic, and information sources about their clinical decisions were collected. Most psychiatrists used second-generation antipsychotics (SGAs), and preferentially an oral formulation, in the treatment of schizophrenia. LAI SGAs were prescribed to 30.4% of schizophrenic patients. The duration and type of practice did not influence the class or formulation of antipsychotics used. The clinicians following the higher percentage of schizophrenic patients were associated with a higher use of LAI antipsychotics and a lower use of oral SGAs. Personal experience, government regulatory approval, and guidelines for the treatment of schizophrenia were the three main contributing factors guiding clinicians' decision-making regarding the treatment of schizophrenia. The more clinicians follow schizophrenic patients, the more they use LAI antipsychotics. The development of specialized programs with top specialists should lead to better use of LAI antipsychotics in the treatment of schizophrenia.


Structure-Activity Relationships of the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PF-46396.
HIV-1 maturation inhibitors are a novel class of antiretroviral compounds that consist of two structurally distinct chemical classes: betulinic acid derivatives and the pyridone-based compound PF-46396. It is currently believed that both classes act by similar modes of action to generate aberrant noninfectious particles via inhibition of CA-SP1 cleavage during Gag proteolytic processing. In this study, we utilized a series of novel analogues with decreasing similarity to PF-46396 to determine the chemical groups within PF-46396 that contribute to antiviral activity, Gag binding, and the relationship between these essential properties. A spectrum of antiviral activity (active, intermediate, and inactive) was observed across the analogue series with respect to CA-SP1 cleavage and HIV-1 (NL4-3) replication kinetics in Jurkat T cells. We demonstrate that selected inactive analogues are incorporated into wild-type (WT) immature particles and that one inactive analogue is capable of interfering with PF-46396 inhibition of CA-SP1 cleavage. Mutations that confer PF-46396 resistance can impose a defective phenotype on HIV-1 that can be rescued in a compound-dependent manner. Some inactive analogues retained the capacity to rescue PF-46396-dependent mutants (SP1-A3V, SP1-A3T, and CA-P157S), implying that they can also interact with mutant Gag. The structure-activity relationships observed in this study demonstrate that (i) the tert-butyl group is essential for antiviral activity but is not an absolute requirement for Gag binding, (ii) the trifluoromethyl group is optimal but not essential for antiviral activity, and (iii) the 2-aminoindan group is important for antiviral activity and Gag binding but is not essential, as its replacement is tolerated. Combinations of antiretroviral drugs successfully treat HIV/AIDS patients; however, drug resistance problems make the development of new mechanistic drug classes an ongoing priority. HIV-1 maturation inhibitors are novel as they target the Gag protein, specifically by inhibiting CA-SP1 proteolytic cleavage. The lack of high-resolution structural information of the CA-SP1 target in Gag has hindered our understanding of the inhibitor-binding pocket and maturation inhibitor mode of action. Therefore, we utilized analogues of the maturation inhibitor PF-46396 as chemical tools to determine the chemical components of PF-46396 that contribute to antiviral activity and Gag binding and the relationship between these essential properties. This is the first study to report structure-activity relationships of the maturation inhibitor PF-46396. PF-46396 is chemically distinct from betulinic acid-derived maturation inhibitors; therefore, our data provide a foundation of knowledge that will aid our understanding of how structurally distinct maturation inhibitors act by similar modes of action.


Remote analysis of biological invasion and the impact of enemy release.
Escape from natural enemies is a widely held generalization for the success of exotic plants. We conducted a large-scale experiment in Hawaii (USA) to quantify impacts of ungulate removal on plant growth and performance, and to test whether elimination of an exotic generalist herbivore facilitated exotic success. Assessment of impacted and control sites before and after ungulate exclusion using airborne imaging spectroscopy and LiDAR, time series satellite observations, and ground-based field studies over nine years indicated that removal of generalist herbivores facilitated exotic success, but the abundance of native species was unchanged. Vegetation cover <1 m in height increased in ungulate-free areas from 48.7% +/- 1.5% to 74.3% +/- 1.8% over 8.4 years, corresponding to an annualized growth rate of lambda = 1.05 +/- 0.01 yr(-1) (median +/- SD). Most of the change was attributable to exotic plant species, which increased from 24.4% +/- 1.4% to 49.1% +/- 2.0%, (lambda = 1.08 +/- 0.01 yr(-1)). Native plants experienced no significant change in cover (23.0% +/- 1.3% to 24.2% +/- 1.8%, lambda = 1.01 +/- 0.01 yr(-1)). Time series of satellite phenology were indistinguishable between the treatment and a 3.0-km2 control site for four years prior to ungulate removal, but they diverged immediately following exclusion of ungulates. Comparison of monthly EVI means before and after ungulate exclusion and between the managed and control areas indicates that EVI strongly increased in the managed area after ungulate exclusion. Field studies and airborne analyses show that the dominant invader was Senecio madagascariensis, an invasive annual forb that increased from < 0.01% to 14.7% fractional cover in ungulate-free areas (lambda = 1.89 +/- 0.34 yr(-1)), but which was nearly absent from the control site. A combination of canopy LAI, water, and fractional cover were expressed in satellite EVI time series and indicate that the invaded region maintained greenness during drought conditions. These findings demonstrate that enemy release from generalist herbivores can facilitate exotic success and suggest a plausible mechanism by which invasion occurred. They also show how novel remote-sensing technology can be integrated with conservation and management to help address exotic plant invasions.


Long noncoding RNAs in mouse embryonic stem cell pluripotency and differentiation.
The transcriptional networks that regulate embryonic stem (ES) cell pluripotency and lineage specification are the subject of considerable attention. To date such studies have focused almost exclusively on protein-coding transcripts. However, recent transcriptome analyses show that the mammalian genome contains thousands of long noncoding RNAs (ncRNAs), many of which appear to be expressed in a developmentally regulated manner. The functions of these remain untested. To identify ncRNAs involved in ES cell biology, we used a custom-designed microarray to examine the expression profiles of mouse ES cells differentiating as embryoid bodies (EBs) over a 16-d time course. We identified 945 ncRNAs expressed during EB differentiation, of which 174 were differentially expressed, many correlating with pluripotency or specific differentiation events. Candidate ncRNAs were identified for further characterization by an integrated examination of expression profiles, genomic context, chromatin state, and promoter analysis. Many ncRNAs showed coordinated expression with genomically associated developmental genes, such as Dlx1, Dlx4, Gata6, and Ecsit. We examined two novel developmentally regulated ncRNAs, Evx1as and Hoxb5/6as, which are derived from homeotic loci and share similar expression patterns and localization in mouse embryos with their associated protein-coding genes. Using chromatin immunoprecipitation, we provide evidence that both ncRNAs are associated with trimethylated H3K4 histones and histone methyltransferase MLL1, suggesting a role in epigenetic regulation of homeotic loci during ES cell differentiation. Taken together, our data indicate that long ncRNAs are likely to be important in processes directing pluripotency and alternative differentiation programs, in some cases through engagement of the epigenetic machinery.


A double layer FSS filter for sub-THz applications.
This work presents the simulated and measured performance of single- and double-layer frequency selective surface filters for operation at sub-THz frequencies (250 GHz center frequency). They were composed of concentric square loops with a split as a unit cell resonator on top of a low dielectric permittivity, low thickness material (RT5880). Both a single layer filter and a cascaded two layer filter with varied distances were investigated. The simulated bandwidth for the cascaded filter was 27 GHz and 16 GHz and 9 GHz bandwidth measured with a THz-TDS and microwave system.


The pathophysiology of migraine: year 2005.
Migraine is a complex patholophysiology in which both central and peripheral components of the trigeminal pain pathway probably play a significant role, both in the symptoms and signs of the attack and in the mechanisms of action of antimigraine compounds, such as triptans, which constitute the most important therapy for aborting migraine pain and possess several mechanisms on 5-HT receptor-mediated actions. The experimental neurogenic inflammation model represents a simple procedure to obtain preliminary information on well characterized receptortargeted drugs. The apparent paradox observed with certain drugs that are shown to be effective in this model but not in clinical trials offers the opportunity to better manipulate structure-activity to obtain the best pharmacological profile using an array of experimental models. The observation that nitric oxide donors induce migraine-like pain in migraineours and that nitric oxide plays a pivotal role in the control of several functions in the central nervous system, has prompted the use of such molecules for better understanding the pathophysiology of migraine attacks. A link between central and peripheral components of the trigeminal pain pathway is provided by the observation that cortical spreading depression in the rat activates trigeminovascular afferents and induces a series of cortical meningeal and brainstem events consistent with the development of headache. Studies in humans support the hypothesis that cortical spreading depression underlies migraine.aura. Therefore, tt is possible that visual, motor or sensory aura might be responsible for the generation of the pain through the above mechanisms.


Evidence for participation by object-selective visual cortex in scene category judgments.
Scene recognition is a core function of the visual system, drawing both on scenes' intrinsic global features, prominently their spatial properties, and on the identities of the objects scenes contain. Neuroimaging and neuropsychological studies have associated spatial property-based scene categorization with parahippocampal cortex, while processing of scene-relevant object information is associated with the lateral occipital complex (LOC), wherein activity patterns distinguish between categories of standalone objects and those embedded in scenes. However, despite the importance of objects to scene categorization and the role of LOC in processing them, damage or disruption to LOC that hampers object recognition has been shown to improve scene categorization. To address this paradox, we used functional magnetic resonance imaging (fMRI) to directly assess the contributions of LOC and the parahippocampal place area (PPA) to category judgments of indoor scenes that were devoid of objective identity signals. Observers were alternately cued to base judgments on scenes' objects or spatial properties. In both LOC and PPA, multivoxel activity patterns better decoded judgments based on their typically associated features: LOC more accurately decoded object-based judgments, while PPA more accurately decoded spatial property-based judgments. The cue contingency of LOC decoding accuracy indicates that it was not an outcome of feedback from judgments and is instead consistent with dependency of judgments on the output of object processing pathways in which LOC participates.


Carcinogenesis Studies of Allyl Isovalerate (CAS No. 2835-39-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Allyl isovalerate, a synthetic fragrance and flavoring ingredient in use since the 1950's, may be found in various products at the following concentrations: soap, 30 ppm; detergent, 3 ppm; creams, 15 ppm; perfume, 50 ppm; nonalcoholic beverages, 9 ppm; ice cream, 18 ppm; candy, 22 ppm; baked goods, 15-48 ppm; and gelatins and puddings, 1 ppm. A colorless liquid with an apple-like odor and taste, allyl isovalerate is approved by the U.S. Food and Drug Administration for use in foods. Specific production figures are not available, but U.S. production in 1980 exceeded 1,000 pounds. Carcinogenesis studies of allyl isovalerate (96% pure) were conducted by administering the test chemical in corn oil gavage to groups of 50 male and 50 female F344/N rats and to groups of 50 male and 50 female B6C3F1 mice at doses of 31 or 62 mg/kg. The doses selected were based on the chemically-induced toxic effects and depressed weight gains obtained from the 13-week studies. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. Survival and mean body weight gain of rats of each sex and male mice were not adversely affected by the administration of allyl isovalerate. The significantly lower survival (P=0.001) and the lower mean body weight of low-dose female as compared with controls are likely consequences of the high incidence of a genital tract infection in the low-dose females. This infection was probably responsible for the deaths of 11/19 control, 22/33 low-dose, and 13/25 high-dose female mice that died before the end of the study. Squamous cell papillomas and epithelial hyperplasia of the nonglandular stomach were observed in dosed male mice in the 2-year studies (squamous cell papillomas: 0/50, 1/50, 2%, 3/48, 6%; epithelial hyperplasia: 1/50, 2%, 1/50, 2%, 7/48, 15%). The papillomas occurred with a significant positive trend (P<0.05). The incidence of high-dose male mice with squamous cell papillomas of the nonglandular stomach was also higher (P<0.01) than the historical rate for vehicle control male B6C3F1 mice in the Bioassay Program (5/881, 0.6%). Forestomach lesions were also observed in female mice: squamous cell papillomas (1/50, 0/50, 2/50) and epithelial hyperplasia of the nonglandular stomach (0/50, 2/50, 3/50). Pancreatic acinar-cell adenomas occurred at higher incidences in the dosed male rats than in the controls (control, 1/50, 2%; low-dose, 4/50, 8%; high-dose, 2/50, 4%). Pancreatic acinar-cell tumors were not observed in female rats. Preputial gland adenomas were observed in increased incidence in low-dose male rats (0/50, 4/50, 8%; P<0.05, 1/50, 2%). Mononuclear-cell leukemias in rats and lymphomas in mice occurred with increased incidences. This consistent dose-response increase among both rats and mice indicates that allyl isovalerate adversely affects the hematopoietic system. Cholangiofibrosis, nodular regeneration, cirrhosis, focal necrosis, fatty metamorphosis, and cytoplasmic vacuolization were observed at increased incidences in the livers of high-dose male and female rats in the 2-year study. No compound-related nonneoplastic lesions were observed in the mice of either sex. Liver neoplasms were not increased in either dosed rats or mice of either sex. Significant (P<0.05) decreases in tumor incidences were observed in male mice for hepatocellular carcinomas (18/50, 6/50, 9/50), for alveolar/bronchiolar adenomas or carcinomas (13/50, 6/50, 5/49), and for follicular-cell adenomas of the thyroid gland (5/47, 0/46, 1/49). Allyl isovalerate was not mutagenic for Salmonella typhimurium (tester strains TA 98, 100, 1535, and 1537) with or without metabolic activation. Under the conditions of these studies, allyl isovalerate was carcinogenic for F344/N rats and B6C3F1 mice, causing increased incidences of hematopoietic system neoplasms (mononuclear-cell leukemia in male rats and lymphoma in female mice). Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negativen female mice). Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Negative Female Mice: Positive


Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK.
Berberine (BBR) has been implicated in bone biology. Although BBR reduces osteoporosis by enhancing BMD and inhibiting osteoclast activity, the effects of BBR on osteoblasts during the process of osteogenesis have not been thoroughly studied. In osteoblastic cells, BBR enhanced the expression of osteogenic marker genes including osteopontin and osteocalcin and promoted the transcriptional activity of the key osteogenic transcription factor Runx2. In osteoblasts, BBR increased the binding of Runx2 to the promoter region of osteopontin. The recruitment of co-factors such as p300 and HDAC1 to the promoter regions of osteopontin and osteocalcin was regulated by BBR, resulting in an enhancement in the expression of those genes. Furthermore, BBR activated p38 mitogen-activated protein kinase (MAPK) and increased cyclooxygenase 2 (COX2) expression, which are key factors in osteoblast differentiation. Consistently, a p38 MAPK-specific inhibitor attenuated the effect of BBR on osteogenesis, whereas p38 MAPK overexpression augmented BBR-induced osteogenic gene expression. Moreover, BBR stimulated bone area formation in calvarial organ culture. Taken together, these findings indicate that BBR promotes osteoblast differentiation through activation of Runx2 by p38 MAPK. Therefore, BBR may be a potential therapeutic agent to treat bone-related disorders including osteoporosis.


Between the town and the mountain: abortion and the politics of life in Edith Wharton's "Summer".
In the early twentieth century, American laws focused on women's reproductive capacities and were coalescing into the ethical and moral frameworks that subtend American reproductive politics today. Edith Wharton published her 1917 novel, Summer, at a time when anti-abortion sentiment was widespread in American culture. Through a reading of Summer, the article provides a theoretical and historical framework for understanding this new American obsession with the judicial regulation of women's reproductive options. In particular, I situate the novel's presentation of abortion within the tension between the carefully defined laws of North Dormer, the town in which the majority of the story takes place, and the lawlessness of the Mountain, a place that looms throughout the story as the protagonist's birthplace and a location of utmost abjection. The novel's profound insight is that power does not function unilaterally and individually but through and on the population. Furthermore, Wharton leaps ahead by recognizing that life is not simply that which lives but that which is recognized and embraced by the law. This realization, one that Wharton must have come to terms with through her painful work with World War I refugees, shapes Charity's character and her understanding not only of how reproduction is regulated but also of how living within this regulation and control generates the norm and offers the only possibility for a liveable and legible life.


Analysis of CD44-hyaluronan interactions in an artificial membrane system: insights into the distinct binding properties of high and low molecular weight hyaluronan.
CD44 is a major cell surface receptor for the large polydisperse glycosaminoglycan hyaluronan (HA). Binding of the long and flexible HA chains is thought to be stabilized by the multivalent nature of the sugar molecule. In addition, high and low molecular weight forms of HA provoke distinct proinflammatory and anti-inflammatory effects upon binding to CD44 and can deliver either proliferative or antiproliferative signals in appropriate cell types. Despite the importance of such interactions, however, neither the stoichiometry of multivalent HA binding at the cell surface nor the molecular basis for functional distinction between different HA size categories is understood. Here we report on the design of a supported lipid bilayer system that permits quantitative analysis of multivalent binding through presentation of CD44 in a stable, natively oriented manner and at controlled density. Using this system in combination with biophysical techniques, we show that the amount of HA binding to bilayers that are densely coated with CD44 increases as a function of HA size, with half-maximal saturation at ∼30 kDa. Moreover, reversible binding was confined to the smaller HA species (molecular weight of ≤10 kDa), whereas the interaction was essentially irreversible with larger polymers. The amount of bound HA decreased with decreasing receptor surface density, but the stability of binding was not affected. From a physico-chemical perspective, the binding properties of HA share many similarities with the typical behavior of a flexible polymer as it adsorbs onto a homogeneously attractive surface. These findings provide new insight into the multivalent nature of CD44-HA interactions and suggest a molecular basis for the distinct biological properties of different size fractions of hyaluronan.


Elder abuse and dementia: a review of the research and health policy.
Older adults with dementia may be at high risk for abuse, but the topic has not been well studied. We conducted a literature review to examine the relationships between elder abuse and dementia. We found that psychological abuse was the most common form of abuse among older adults, with estimates of its prevalence ranging from 27.9 percent to 62.3 percent. Physical abuse was estimated to affect 3.5-23.1 percent of older adults with dementia. We also found that many older adults experienced multiple forms of abuse simultaneously, and the risk of mortality from abuse and self-neglect may be higher in older adults with greater levels of cognitive impairment. We summarize programs and policies related to the abuse of older adults with dementia, including adult protective services, mandatory elder abuse reporting, and the Long-Term Care Ombudsman Program. We also summarize aspects of the National Alzheimer's Project Act, the Older Americans Act, and the Elder Justice Act. In spite of a recent increase in research and policy developments on elder abuse, challenges such as insufficient funding, limited knowledge about elder abuse, a lack of funding for the implementation of federal and state programs relevant to elder abuse and dementia, and a lack of dementia-specific training for front-line health care staff persist. Stronger programs targeting the well-being of older adults with dementia are needed.


Inequity in palliative care service full utilisation among patients with advanced cancer: a retrospective Cohort study.
Background: Advanced cancer patients often die in hospital after receiving needless, aggressive treatment. Although palliative care improves symptom management, barriers to accessing palliative care services affect its utilisation, and such disparities challenge the equitable provision of palliative care. This study aimed to identify which factors are associated with inequitable palliative care service utilisation among advanced cancer patients by applying the Andersen Behavioural Model of Health Services Use.Material and methods: This was a retrospective cohort study using administrative healthcare data. A total of 13,656 patients residing in the Lazio region of Italy, who died of an advanced cancer-related cause-either in hospital or in a specialised palliative care facility-during the period of 2012-2016 were included in the study. Potential predictors of specialised palliative service utilisation were explored by grouping the following factors: predisposing factors (i.e., individuals' characteristics), enabling factors (i.e., systemic/structural factors) and need factors (i.e., type/severity of illness).Results: The logistic hierarchical regression showed that older patients (odds ratio [OR] = 1.45; <0.0001) of Caucasian ethnicity (OR = 4.17; 0.02), with a solid tumour (OR = 1.87; <0.0001) and with a longer survival time (OR = 2.09; <0.0001) were more likely to be enrolled in a palliative care service. Patients who lived farther from a specialised palliative care facility (OR = 0.13; <0.0001) and in an urban area (OR = 0.58; <0.0001) were less likely to be enrolled.Conclusion: This study found that socio-demographic (age, ethnicity), clinical (type of tumour, survival time) and organisational (area of residence, distance from service) factors affect the utilisation of specialised palliative care services. The fact that service utilisation is not only a function of patients' needs but also of other aspects demonstrates the presence of inequity in access to palliative care among advanced cancer patients.


Wheat cytosolic acetyl-CoA carboxylase complements an ACC1 null mutation in yeast.
Spores harboring an ACC1 deletion derived from a diploid Saccharomyces cerevisiae strain, in which one copy of the entire ACC1 gene is replaced with a LEU2 cassette, fail to grow. A chimeric gene consisting of the yeast GAL10 promoter, yeast ACC1 leader, wheat cytosolic acetyl-CoA carboxylase (ACCase) cDNA, and yeast ACC1 3' tail was used to complement a yeast ACC1 mutation. The complementation demonstrates that active wheat ACCase can be produced in yeast. At low concentrations of galactose, the activity of the "wheat gene" driven by the GAL10 promoter is low and ACCase becomes limiting for growth, a condition expected to enhance transgenic yeast sensitivity to wheat ACCase-specific inhibitors. An aryloxyphenoxypropionate and two cyclohexanediones do not inhibit growth of haploid yeast strains containing the yeast ACC1 gene, but one cyclohexanedione inhibits growth of the gene-replacement strains at concentrations below 0.2 mM. In vitro, the activity of wheat cytosolic ACCase produced by the gene-replacement yeast strain is inhibited by haloxyfop and cethoxydim at concentrations above 0.02 mM. The activity of yeast ACCase is less affected. The wheat plastid ACCase in wheat germ extract is inhibited by all three herbicides at concentrations below 0.02 mM. Yeast gene-replacement strains will provide a convenient system for the study of plant ACCases.


Mapping the binding site for the GTP-binding protein Rac-1 on its inhibitor RhoGDI-1.
Members of the Rho family of small GTP-binding proteins, such as Rho, Rac and Cdc42, have a role in a wide range of cell responses. These proteins function as molecular switches by virtue of a conformational change between the GTP-bound (active) and GDP-bound (inactive) forms. In addition, most members of the Rho and Rac subfamilies cycle between the cytosol and membrane. The cytosolic guanine nucleotide dissociation inhibitors, RhoGDIs, regulate both the GDP/GTP exchange cycle and the membrane association/dissociation cycle. We have used NMR spectroscopy and site-directed mutagenesis to identify the regions of human RhoGDI-1 that are involved in binding Rac-1. The results emphasise the importance of the flexible regions of both proteins in the interaction. At least one specific region (residues 46-57) of the flexible N-terminal domain of RhoGDI, which has a tendency to form an amphipathic helix in the free protein, makes a major contribution to the binding energy of the complex. In addition, the primary site of Rac-1 binding on the folded domain of RhoGDI involves the beta4-beta5 and beta6-beta7 loops, with a slight movement of the 3(10) helix accompanying the interaction. This binding site is on the same face of the protein as the binding site for the isoprenyl group of post-translationally modified Rac-1, but is distinct from this site. Isoprenylated Rac-1 appears to interact with three distinct sites on RhoGDI. The isoprenyl group attached to the C terminus of Rac-1 binds in a pocket in the folded domain of RhoGDI. This is distinct from the major site on this domain occupied by Rac-1 itself, which involves two loops at the opposite end to the isoprenyl-binding site. It is probable that the flexible C-terminal region of Rac-1 extends from the site at which Rac-1 contacts the folded domain of RhoGDI to allow the isoprenyl group to bind in the pocket at the other end of the RhoGDI molecule. Finally, the flexible N terminus of RhoGDI-1, and particularly residues 48-58, makes a specific interaction with Rac-1 which contributes substantially to the binding affinity.


Differential Expression of Long Noncoding RNAs Reveals a Potential Biomarker for Intractable Pemphigus.
Long noncoding RNAs (lncRNAs) are involved in autoimmune diseases. However, the role of lncRNAs in pemphigus remains elusive. The study is aimed at investigating the expression profile in pemphigus patients to identify a circulating lncRNA as a novel biomarker for pemphigus. A global lncRNA expression profile in peripheral blood mononuclear cells (PBMCs) was measured by lncRNA microarray. Differentially expressed lncRNAs were validated by quantitative reverse transcriptase-PCR (qRT-PCR). The functional and biological processes of the differentially expressed lncRNAs were analyzed by bioinformatics. lncRNA ENST00000585297 in the PBMCs of pemphigus patients was highly expressed compared with those of HCs and BP patients. The area under the receiver operating characteristic (ROC) curve was 0.846 (95%confidence interval (CI) = 0.7526 to 0.9397). Intriguingly, we found that the expression of ENST00000585297 was upregulated in pemphigus patients whose symptoms could not be managed within four weeks compared to other patients whose symptoms could be managed in four weeks or less (P < 0.05). In addition, ENST00000585297 expression in pemphigus patients was positively correlated with the dosage of prednisone needed to manage the disorder (r = 0.4905, P = 0.0094). A competing endogenous RNA (ceRNA) regulatory network was constructed based on the ceRNA theory. Further verification demonstrated that silencing of ENST00000585297 increased the expression of miR-584-3p. Our study revealed for the first time the expression profile of lncRNAs in pemphigus patients. In addition, our study identified ENST00000585297 as a biomarker and indicator for the intractable course of pemphigus.


High perceived stress and social interaction behaviour among young adults. A study based on objective measures of face-to-face and smartphone interactions.
Stress and mental health problems impede social functioning and may also complicate relationship formation with peers. The aim was to investigate whether high perceived stress among young adults is associated with social interaction behaviour both via face-to-face interaction and via smartphone interaction. The data was derived from the Copenhagen Network Study, where 535 first-year students (mean age 21.3, 77% male) self-reported on perceived stress at baseline and were subsequently followed for three months with continuous Bluetooth recordings of face-to-face interactions and smartphone interactions (calls and texts) measuring the network size, frequency, and duration of interactions. Logistic regression was used to assess associations between perceived stress (high/low) and social interactions adjusting for sex, age, and personality traits. Participants with high perceived stress were more likely to engage in a larger call and text network and have a higher call and text frequency compared to individuals with low perceived stress. We found a non-statistically significant tendency that participants with a high perceived stress level spend less time meeting face to face with peers. Stressed students engage in frequent smartphone interaction which may be explained by a social support seeking behaviour, or it may be that accommodating a large network via the smartphone is stress-inducing.


Factors affecting use of unscheduled care for people with advanced cancer: a retrospective cohort study in Scotland.
People with advanced cancer frequently attend unscheduled care, but little is known about the factors influencing presentations. Most research focuses on accident and emergency (A&E) and does not consider GP out-of-hours (GPOOH). To describe the frequency and patterns of unscheduled care use by people with cancer in their last year of life and to examine the associations of demographic and clinical factors with unscheduled care attendance. Retrospective cohort study of all 2443 people who died from cancer in Tayside, Scotland, during 2012-2015. Clinical population datasets were linked to routinely collected clinical data using the Community Health Index (CHI) number. Anonymised CHI-linked data were analysed in SafeHaven, with descriptive analysis, using binary logistic regression for adjusted associations. Of the people who died from cancer, 77.9% (n = 1904) attended unscheduled care in the year before death. Among unscheduled care users, most only attended GPOOH (n = 1070, 56.2%), with the rest attending A&E only (n = 204, 10.7%), or both (n = 630, 33.1%). Many attendances occurred in the last week (n =1360, 19.7%), last 4 weeks (n = 2541, 36.7%), and last 12 weeks (n = 4174, 60.3%) of life. Age, sex, deprivation, and cancer type were not significantly associated with unscheduled care attendance. People living in rural areas were less likely to attend unscheduled care: adjusted odds ratio (aOR) 0.64 (95% confidence interval = 0.50 to 0.82). Pain was the commonest coded clinical reason for presenting (GPOOH: n = 482, 10.5%; A&E: n = 336, 28.8%). Of people dying from cancer, n = 514, 21.0%, were frequent users (≥5 attendances/year), and accounted for over half (n = 3986, 57.7%) of unscheduled care attendances. Unscheduled care attendance by people with advanced cancer was substantially higher than previously reported, increased dramatically towards the end of life, was largely independent of demographic factors and cancer type, and was commonly for pain and palliative care.


Trends in Costs of Thyroid Disease Treatment in Denmark during 1995-2015.
Iodine fortification (IF) may contribute to changes in costs of thyroid disease treatment through changes in disease patterns. From a health economic perspective, assessment of the development in costs of thyroid disease treatment in the population is pertinent. To assess the trends in annual medicine and hospital costs of thyroid disease treatment during 1995-2015 in Denmark, i.e., before and after the introduction of mandatory IF in 2000. Information on treatments for thyroid disease (antithyroid medication, thyroid hormone therapy, thyroid surgery, and radioiodine treatment) was obtained from nationwide registers. Costs were valued at 2015 prices using sales prices for medicines and the Danish Diagnosis-Related Group (DRG) and Danish Ambulatory Grouping System (DAGS) tariffs of surgeries/radioiodine treatments. Results were adjusted for changes in population size and age and sex distribution. The total direct medicine and hospital costs of thyroid disease treatment increased from EUR ∼190,000 per 100,000 persons in 1995 to EUR ∼270,000 per 100,000 persons in 2015. This was mainly due to linearly increased costs of thyroid hormone therapy and increased costs of thyroid surgery since 2008. Costs of antithyroid medication increased slightly and transiently after IF, while costs of radioiodine treatment remained constant. Costs of thyroid hormone therapy and thyroid surgery did not follow the development in the prevalence of hypothyroidism and structural thyroid diseases observed in concurrent studies. The costs of total direct medicine and hospital costs for thyroid disease treatment in Denmark increased from 1995 to 2015. This is possibly due to several factors, e.g., changes in treatment practices, and the direct effect of IF alone remains to be estimated.


Statistical reviewers improve reporting in biomedical articles: a randomized trial.
Although peer review is widely considered to be the most credible way of selecting manuscripts and improving the quality of accepted papers in scientific journals, there is little evidence to support its use. Our aim was to estimate the effects on manuscript quality of either adding a statistical peer reviewer or suggesting the use of checklists such as CONSORT or STARD to clinical reviewers or both. Interventions were defined as 1) the addition of a statistical reviewer to the clinical peer review process, and 2) suggesting reporting guidelines to reviewers; with "no statistical expert" and "no checklist" as controls. The two interventions were crossed in a 2x2 balanced factorial design including original research articles consecutively selected, between May 2004 and March 2005, by the Medicina Clinica (Barc) editorial committee. We randomized manuscripts to minimize differences in terms of baseline quality and type of study (intervention, longitudinal, cross-sectional, others). Sample-size calculations indicated that 100 papers provide an 80% power to test a 55% standardized difference. We specified the main outcome as the increment in quality of papers as measured on the Goodman Scale. Two blinded evaluators rated the quality of manuscripts at initial submission and final post peer review version. Of the 327 manuscripts submitted to the journal, 131 were accepted for further review, and 129 were randomized. Of those, 14 that were lost to follow-up showed no differences in initial quality to the followed-up papers. Hence, 115 were included in the main analysis, with 16 rejected for publication after peer review. 21 (18.3%) of the 115 included papers were interventions, 46 (40.0%) were longitudinal designs, 28 (24.3%) cross-sectional and 20 (17.4%) others. The 16 (13.9%) rejected papers had a significantly lower initial score on the overall Goodman scale than accepted papers (difference 15.0, 95% CI: 4.6-24.4). The effect of suggesting a guideline to the reviewers had no effect on change in overall quality as measured by the Goodman scale (0.9, 95% CI: -0.3-+2.1). The estimated effect of adding a statistical reviewer was 5.5 (95% CI: 4.3-6.7), showing a significant improvement in quality. This prospective randomized study shows the positive effect of adding a statistical reviewer to the field-expert peers in improving manuscript quality. We did not find a statistically significant positive effect by suggesting reviewers use reporting guidelines.


Reverse use dependence of Kv4.2 blockade by 4-aminopyridine.
4-Aminopyridine (4AP) can block various K channels with different state dependences; block occurs in the activated state or in the closed state. The use of K channel clones to study the mechanism and structural determinants responsible for the state dependence of 4AP actions has been hampered by the fact that, for all the K channel clones examined so far, 4AP binding and unbinding occur mainly in the activated state. We report here that 4AP binding to a fast inactivating K channel encoded by Kv4.2 in Xenopus oocytes occurred exclusively in the closed state. The binding rate was slow and independent of membrane voltage in the range from -80 to -120 mV. The binding rate was linearly related to 4AP concentration, yielding apparent binding and unbinding rate constants of 0.012 mM-1 s-1 and 0.062 s-1, respectively. 4AP dissociation from Kv4.2 occurred in two processes, a slow process in the closed state (in a voltage range from -70 to -40 mV) and a fast process in the activated state, which suggested that the closure of the activation gate of Kv4.2 did not prevent the entry or exit of 4AP molecules but slowed these processes. 4AP slowed the rate of Kv4.2 decay during depolarization, consistent with the notion that channel inactivation occurred only after 4AP dissociation. Inactivating Kv4.2 channels prevented 4AP binding. Therefore, 4AP binding and Kv4.2 inactivation were mutually exclusive. This, in conjunction with the observation that 4AP blocked Kv4.2 channels from the intracellular side of the cell membrane, suggests that the 4AP binding site is on the cytoplasmic surface of the Kv4.2 channel at, or adjacent to, the domains involved in channel inactivation. The distinct features of 4AP actions on the time course of transient outward current in human ventricular myocytes suggest that Kv4.2-like subunits are important in the formation of these channels in human heart.


Harnessing employment-based social assistance programmes to scale up nature-based climate action.
As the severity of the triple challenges of global inequality, climate change and biodiversity loss becomes clearer, governments and international development institutions must find effective policy instruments to respond. We examine the potential of social assistance policies in this context. Social assistance refers to transfers to poor, vulnerable and marginalized groups to reduce their vulnerability and livelihood risks, and to enhance their rights and status. Substantial public funds support social assistance programmes globally. Collectively, lower- and middle-income countries spend approximately 1.5% of their GDP on social assistance annually. We focus on the potential of paid employment schemes to promote effective ecosystem stewardship. Available evidence suggests such programmes can offer multiple benefits in terms of improvements in local ecosystems and natural capital, carbon sequestration and local biodiversity conservation. We review evidence from three key case studies: in India (the Mahatma Gandhi National Rural Employment Guarantee Scheme), Ethiopia (the Productive Safety Nets Programme) and Mexico (the Temporary Employment Programme). We conclude that, to realize the potential of employment-based social assistance for ecosystem benefits it will be necessary to address two challenges: first, the weak design and maintenance of local public works outputs in many schemes, and second, the concern that social protection schemes may become less effective if they are overburdened with additional objectives. Overcoming these challenges requires an evolution of institutional systems for delivering social assistance to enable a more effective combination of social and environmental objectives. This article is part of the theme issue 'Climate change and ecosystems: threats, opportunities and solutions'.


Variability in bimanual wheelchair propulsion: consistency of two instrumented wheels during handrim wheelchair propulsion on a motor driven treadmill.
Handrim wheelchair propulsion is a complex bimanual motor task. The bimanually applied forces on the rims determine the speed and direction of locomotion. Measurements of forces and torques on the handrim are important to study status and change of propulsion technique (and consequently mechanical strain) due to processes of learning, training or the wheelchair configuration. The purpose of this study was to compare the simultaneous outcomes of two different measurement-wheels attached to the different sides of the wheelchair, to determine measurement consistency within and between these wheels given the expected inter- and intra-limb variability as a consequence of motor control. Nine able-bodied subjects received a three-week low-intensity handrim wheelchair practice intervention. They then performed three four-minute trials of wheelchair propulsion in an instrumented hand rim wheelchair on a motor-driven treadmill at a fixed belt speed. The two measurement-wheels on each side of the wheelchair measured forces and torques of one of the two upper limbs, which simultaneously perform the push action over time. The resulting data were compared as direct output using cross-correlation on the torque around the wheel-axle. Calculated push characteristics such as power production and speed were compared using an intra-class correlation. Measured torque around the wheel axle of the two measurement-wheels had a high average cross-correlation of 0.98 (std=0.01). Unilateral mean power output over a minute was found to have an intra-class correlation of 0.89 between the wheels. Although the difference over the pushes between left and right power output had a high variability, the mean difference between the measurement-wheels was low at 0.03 W (std=1.60). Other push characteristics showed even higher ICC's (>0.9). A good agreement between both measurement-wheels was found at the level of the power output. This indicates a high comparability of the measurement-wheels for the different propulsion parameters. Data from both wheels seem suitable to be used together or interchangeably in experiments on motor control and wheelchair propulsion performance. A high variability in forces and timing between the left and right side were found during the execution of this bimanual task, reflecting the human motor control process.


Associations of Health Club Membership with Physical Activity and Cardiovascular Health.
This study evaluates whether a health club membership is associated with meeting the US physical activity (PA) guidelines and/or favorable cardiovascular health. Using cross-sectional data of health club members (n = 204) and non-members (n = 201) from April to August 2013, this is the first study to our knowledge to examine a health club membership in relation to objectively measured cardiovascular health indicators including resting blood pressure, resting heart rate, body mass index, waist circumference, and cardiorespiratory fitness based on a non-exercise test algorithm. To determine the total PA and sedentary time, this study used a comprehensive PA questionnaire about both aerobic and resistance activities at the health club, as well as lifestyle activities in other settings, which was developed based on the International Physical Activity Questionnaire (IPAQ). The odds ratios (95% confidence interval) of meeting either the aerobic, resistance, or both aerobic and resistance PA guidelines for members compared to non-members were 16.5 (9.8-27.6), 10.1 (6.2-16.3), and 13.8 (8.5-22.4), respectively. Significant associations of health club membership with more favorable cardiovascular health outcomes and sedentary behavior were observed for resting heart rate (B: -4.8 b/min, p<0.001), cardiorespiratory fitness (B: 2.1 ml/kg/min, p<0.001), and sedentary time (B: -1.4 hours, p<0.001). Participants with a health club membership of >1 year had more favorable health outcomes, with a smaller waist circumference (men, B: -4.0 cm, p = 0.04; women, B: -3.4 cm, p = 0.06), compared to non-members. Health club membership is associated with significantly increased aerobic and resistance physical activity levels and more favorable cardiovascular health outcomes compared to non-members. However, longitudinal, randomized controlled trials would be clearly warranted as cross-sectional data prohibits causal inferences.


Inter-laboratory assessment of different digital PCR platforms for quantification of human cytomegalovirus DNA.
Quantitative PCR (qPCR) is an important tool in pathogen detection. However, the use of different qPCR components, calibration materials and DNA extraction methods reduces comparability between laboratories, which can result in false diagnosis and discrepancies in patient care. The wider establishment of a metrological framework for nucleic acid tests could improve the degree of standardisation of pathogen detection and the quantification methods applied in the clinical context. To achieve this, accurate methods need to be developed and implemented as reference measurement procedures, and to facilitate characterisation of suitable certified reference materials. Digital PCR (dPCR) has already been used for pathogen quantification by analysing nucleic acids. Although dPCR has the potential to provide robust and accurate quantification of nucleic acids, further assessment of its actual performance characteristics is needed before it can be implemented in a metrological framework, and to allow adequate estimation of measurement uncertainties. Here, four laboratories demonstrated reproducibility (expanded measurement uncertainties below 15%) of dPCR for quantification of DNA from human cytomegalovirus, with no calibration to a common reference material. Using whole-virus material and extracted DNA, an intermediate precision (coefficients of variation below 25%) between three consecutive experiments was noted. Furthermore, discrepancies in estimated mean DNA copy number concentrations between laboratories were less than twofold, with DNA extraction as the main source of variability. These data demonstrate that dPCR offers a repeatable and reproducible method for quantification of viral DNA, and due to its satisfactory performance should be considered as candidate for reference methods for implementation in a metrological framework.


Fitness, fatness, cognition, behavior, and academic achievement among overweight children: do cross-sectional associations correspond to exercise trial outcomes?
This study examined associations of fitness and fatness with cognitive processes, academic achievement, and behavior, independent of demographic factors, at the baseline of an exercise trial. Overweight, sedentary but otherwise healthy 7-11 year olds (N=170) participated in a study of health, cognition and achievement in the Augusta, GA area from 2003-2006. Children underwent evaluations of fatness and fitness, psychological assessments of cognition and academic achievement, and behavior ratings by parents and teachers. Partial correlations examined associations of fitness and fatness with cognitive and achievement scores and behavior ratings, controlling for demographic factors. Fitness was associated with better cognition, achievement and behavior, and fatness with worse scores. Specifically, executive function, mathematics and reading achievement, and parent ratings of child behavior were related to fitness and fatness. Teacher ratings were related to fitness. These results extend prior studies by providing reliable, standardized measures of cognitive processes, achievement, and behavior in relation to detailed measures of fitness and fatness. However, cross-sectional associations do not necessarily indicate that improving one factor, such as fatness or fitness, will result in improvements in factors that were associated with it. Thus, randomized clinical trials are necessary to determine the effects of interventions.


Is the chronic Tier-1 effect assessment approach for insecticides protective for aquatic ecosystems?
We investigated the appropriateness of several methods, including those recommended in the Aquatic Guidance Document of the European Food Safety Authority (EFSA), for the derivation of chronic Tier-1 regulatory acceptable concentrations (RACs) for insecticides and aquatic organisms. The insecticides represented different chemical classes (organophosphates, pyrethroids, benzoylureas, insect growth regulators, biopesticides, carbamates, neonicotinoids, and miscellaneous). Chronic Tier-1 RACs derived using toxicity data for the standard species Daphnia magna, Chironomus spp., and/or Americamysis bahia, were compared with Tier-3 RACs derived from micro- and mesocosm studies on basis of the ecological threshold option (ETO-RACs). ETO-RACs could be derived for 31 insecticides applied to micro- and mesocosms in single or multiple applications, yielding a total number of 36 cases for comparison. The chronic Tier-1 RACs calculated according to the EFSA approach resulted in a sufficient protection level, except for 1 neonicotinoid (slightly underprotective) and for several pyrethroids if toxicity data for A. bahia were not included. This latter observation can be explained by 1) the fact that A. bahia is the most sensitive standard test species for pyrethroids, 2) the hydrophobic properties of pyrethroids, and 3) the fact that long-term effects observed in (epi) benthic arthropods may be better explained by exposure via the sediment than via overlying water. Besides including toxicity data for A. bahia, the protection level for pyrethroids can be improved by selecting both D. magna and Chironomus spp. as standard test species for chronic Tier-1 derivation. Although protective in the majority of cases, the conservativeness of the recommended chronic Tier-1 RACs appears to be less than an order of magnitude for a relatively large proportion of insecticides when compared with their Tier-3 ETO-RACs. This may leave limited options for refinement of the chronic effect assessment using laboratory toxicity data for additional species. Integr Environ Assess Manag 2016;12:747-758. © 2015 SETAC.


Inflammatory Markers and Risk of Epithelial Ovarian Cancer by Tumor Subtypes: The EPIC Cohort.
Evidence suggests an etiologic role for inflammation in ovarian carcinogenesis and heterogeneity between tumor subtypes and anthropometric indices. Prospective studies on circulating inflammatory markers and epithelial invasive ovarian cancer (EOC) have predominantly investigated overall risk; data characterizing risk by tumor characteristics (histology, grade, stage, dualistic model of ovarian carcinogenesis) and anthropometric indices are sparse. We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate C-reactive protein (CRP), IL6, and EOC risk by tumor characteristics. A total of 754 eligible EOC cases were identified; two controls (n = 1,497) were matched per case. We used multivariable conditional logistic regression to assess associations. CRP and IL6 were not associated with overall EOC risk. However, consistent with prior research, CRP >10 versus CRP ≤1 mg/L was associated with higher overall EOC risk [OR, 1.67 (1.03-2.70)]. We did not observe significant associations or heterogeneity in analyses by tumor characteristics. In analyses stratified by waist circumference, inflammatory markers were associated with higher risk among women with higher waist circumference; no association was observed for women with normal waist circumference [e.g., IL6: waist ≤80: ORlog2, 0.97 (0.81-1.16); waist >88: ORlog2, 1.78 (1.28-2.48), Pheterogeneity ≤ 0.01]. Our data suggest that high CRP is associated with increased risk of overall EOC, and that IL6 and CRP may be associated with EOC risk among women with higher adiposity. Our data add to global evidence that ovarian carcinogenesis may be promoted by an inflammatory milieu.


Telesonography in emergency medicine: A systematic review.
Ultrasound is an efficacious, versatile and affordable imaging technique in emergencies, but has limited utility without expert interpretation. Telesonography, in which experts may remotely support the use of ultrasound through a telecommunications link, may broaden access to ultrasound and improve patient outcomes, particularly in remote settings. This review assesses the literature regarding telesonography in emergency medicine, focussing on evidence of feasibility, diagnostic accuracy and clinical utility. A systematic search was performed for articles published from 1946 to February 2017 using the Cochrane, Medline, EMBASE, and CINAHL databases. Further searches utilising Scopus, Google Scholar, and citation lists were conducted. 4388 titles were identified and screened against inclusion criteria which resulted in the inclusion of 28 papers. These included feasibility, diagnostic accuracy and clinical pilot studies. Study design, methodology and quality were heterogeneous. There was good evidence of feasibility from multiple studies. Where sufficient bandwidth and high quality components were used, diagnostic accuracy was slightly reduced by image transmission. There was evidence of clinical utility in remote hospitals and low-resource settings, although reliability was infrequently reported. Further exploratory research is required to determine minimum requirements for image quality, bandwidth, frame rate and to assess diagnostic accuracy. Clinical trials in remote settings are justifiable. Telecommunication options will depend on local requirements; no one system conveys universal advantages. The methodological quality of research in this field must improve: studies should be designed to minimise bias, and must include details of their methods to allow replication. Analysis of cost effectiveness and sustainability should be provided.


A neural learning classifier system with self-adaptive constructivism for mobile robot control.
For artificial entities to achieve true autonomy and display complex lifelike behavior, they will need to exploit appropriate adaptable learning algorithms. In this context adaptability implies flexibility guided by the environment at any given time and an open-ended ability to learn appropriate behaviors. This article examines the use of constructivism-inspired mechanisms within a neural learning classifier system architecture that exploits parameter self-adaptation as an approach to realize such behavior. The system uses a rule structure in which each rule is represented by an artificial neural network. It is shown that appropriate internal rule complexity emerges during learning at a rate controlled by the learner and that the structure indicates underlying features of the task. Results are presented in simulated mazes before moving to a mobile robot platform.


E-cadherin-coated plates maintain pluripotent ES cells without colony formation.
Embryonic stem (ES) cells cultured on gelatin-coated plates or feeder layers form tight aggregated colonies by the E-cadherin-mediated cell-cell adhesions. Here we show that murine ES cells do not make cell-cell contacts or form colonies when cultured on the plate coated with a fusion protein of E-cadherin and IgG Fc domain. The cells in culture retain all ES cell features including pluripotency to differentiate into cells of all three germ layers and germ-line transmission after extended culture. Furthermore, they show a higher proliferative ability, lower dependency on LIF, and higher transfection efficiency than colony-forming conditions. Our results suggest that aggregated colony formation might inhibit diffusion of soluble factors and increase cell-cell communication, which may result in a heterogeneous environment within and between surrounding cells of the colony. This method should enable more efficient and scalable culture of ES cells, an important step towards the clinical application of these cells.


Prognostic value of baseline plasma amino-terminal pro-brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial.
Plasma concentrations of natriuretic peptides (NPs) are associated with morbidity and mortality in patients with systolic heart failure (HF). However, the role of NP as a prognostic marker in patients with HF and preserved ejection fraction (HFpEF) has not been studied in a large cohort of well-characterized patients. Moreover, it is unclear whether treatments have a differential effect on morbidity and mortality across the spectrum of NP levels. N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured at baseline in 3480 patients in the I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Trial). In a multivariable Cox regression model, NT-proBNP above the median of 339 pg/mL was independently associated with an increased risk of the primary end point of all-cause mortality and prespecified cardiovascular hospitalizations (adjusted hazard ratio [HR], 1.79; 95% CI, 1.56 to 2.10; P<0.001); all-cause mortality (adjusted HR, 2.04; 95% CI, 1.68 to 2.47; P<0.001); and a composite of HF events, including death due to worsening HF or sudden death or hospitalization due to worsening HF (adjusted HR, 1.77; 95% CI, 1.43 to 2.20; P<0.001). There were significant interactions between the effect of irbesartan and median split of baseline NT-proBNP for the primary outcome (P=0.005), all-cause mortality (P=0.05), and the HF composite outcome (P<0.001). Use of irbesartan was associated with improved outcomes in patients with NT-proBNP below, but not above, the median. After adjusting for 20 baseline covariates, irbesartan still had a beneficial effect on the primary outcome (HR, 0.74; 95% CI, 0.60 to 90; P=0.003), all-cause mortality (HR, 0.75; 95% CI, 0.56 to 0.99; P=0.046), and HF composite outcome (HR, 0.57; 95% CI, 0.41 to 0.80; P=0.001) in patients with NT-proBNP below the median. The unexpected benefit of irbesartan in lower-risk patients with HFpEF in this post hoc analysis may indicate effects on early, but not later, high-risk stages of the disease. These findings question the strategy of using elevated plasma concentrations of NP as a patient selection criterion in HFpEF trials. More studies are needed to support or contest this practice. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.


Triple-negative pleomorphic lobular carcinoma and expression of androgen receptor: Personal case series and review of the literature.
Pleomorphic lobular carcinoma (PLC) is a histological variant of invasive lobular carcinoma (ILC) and is associated with worse prognosis than classical ILC. It exhibits a greater degree of cellular atypia and pleomorphism and is occasionally accompanied with apocrine morphology. We investigated the immunohistochemical characteristics of samples from 31 Japanese patients with PLC to elucidate the clinicopathological characteristics of PLC including androgen receptor (AR) immunoreactivity. The surrogate molecular subtypes were luminal A-like, luminal B-like, luminal B-like/HER2, HER2-type, and triple-negative in 5, 4, 3, 5, and 14 cases, respectively. AR was positive in 92.8% (13/14) of the triple-negative PLC cases and 100% (10/10) of the non-triple-negative PLC cases. Disease-specific survival was worse in patients with histological grade 3 PLCs than in those with histological grade 2 PLCs (p = 0.007). However, there was no significant difference in the progression-free survival between the two groups (p = 0.152). No other clinicopathological characteristics were associated with prognosis. These results reveal that PLC exhibits various surrogate molecular subtypes and that the triple-negative subtype frequently expresses AR. The observed molecular apocrine differentiation implicates that triple-negative PLC can be categorized into the luminal AR subtype. Furthermore, AR-targeted therapy might be useful for patients with triple-negative PLC.