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  • 1
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-06
    Description: by Bo Hyon Yun, Seung Joo Chon, Young Sik Choi, SiHyun Cho, Byung Seok Lee, Seok Kyo Seo
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 2
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-06
    Description: by Tenglong Xie, Wanrong Gu, Liguo Zhang, Lijie Li, Danyang Qu, Caifeng Li, Yao Meng, Jing Li, Shi Wei, Wenhua Li Maize ( Zea mays L.), an important agricultural crop, suffers from drought stress frequently during its growth period, thus leading to a decline in yield. 2-(3,4-Dichlorophenoxy) triethylamine (DCPTA) regulates many aspects of plant development; however, its effects on crop stress tolerance are poorly understood. We pre-treated maize seedlings by adding DCPTA to a hydroponic solution and then subjected the seedlings to a drought condition [15% polyethylene glycol (PEG)-6000 treatment]. The activities of superoxide dismutase (SOD), peroxidase (POD), ascorbate peroxidase (APX), and glutathione reductase (GR) were enhanced under drought stress and further enhanced by the DCPTA application. The activities of monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR) and catalase (CAT) declined continuously under drought stress; however, the activities partially recovered with DCPTA application. Up-regulation of the activities and transcript levels of APX, GR, MDHAR and DHAR in the DCPTA treatments contributed to the increases in ascorbate (AsA) and glutathione (GSH) levels and inhibited the increased generation rate of superoxide anion radicals (O 2 · − ), the contents of hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA), and the electrolyte leakage (EL) induced by drought. These results suggest that the enhanced antioxidant capacity induced by DCPTA application may represent an efficient mechanism for increasing the drought stress tolerance of maize seedlings.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 3
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-06
    Description: by Elmar Kal, Rens Prosée, Marinus Winters, John van der Kamp Background Implicit motor learning is considered to be particularly effective for learning sports-related motor skills. It should foster movement automaticity and thereby facilitate performance in multitasking and high-pressure environments. To scrutinize this hypothesis, we systematically reviewed all studies that compared the degree of automatization achieved (as indicated by dual-task performance) after implicit compared to explicit interventions for sports-related motor tasks. Methods For this systematic review (CRD42016038249) conventional (MEDLINE, CENTRAL, Embase, PsycINFO, SportDiscus, Web of Science) and grey literature were searched. Two reviewers independently screened reports, extracted data, and performed risk of bias assessment. Implicit interventions of interest were analogy-, errorless-, dual-task-, and external focus learning. Data analysis involved descriptive synthesis of group comparisons on absolute motor dual-task (DT) performance, and motor DT performance relative to single-task motor performance (motor DTCs). Results Of the 4125 reports identified, we included 25 controlled trials that described 39 implicit-explicit group comparisons. Risk of bias was unclear across trials. Most comparisons did not show group differences. Some comparisons showed superior absolute motor DT performance (N = 2), superior motor DTCs (N = 4), or both (N = 3) for the implicit compared to the explicit group. The explicit group showed superior absolute motor DT performance in two comparisons. Conclusions Most comparisons did not show group differences in automaticity. The remaining comparisons leaned more toward a greater degree of movement automaticity after implicit learning than explicit learning. However, due to an overall unclear risk of bias the strength of the evidence is level 3. Motor learning-specific guidelines for design and especially reporting are warranted to further strengthen the evidence and facilitate low-risk-of-bias trials.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 4
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-06
    Description: by Merel Maslowski, Antje S. Meyer, Hans Rutger Bosker Listeners are known to use adjacent contextual speech rate in processing temporally ambiguous speech sounds. For instance, an ambiguous vowel between short /α/ and long /a:/ in Dutch sounds relatively long (i.e., as /a:/) embedded in a fast precursor sentence, but short in a slow sentence. Besides the local speech rate, listeners also track talker-specific global speech rates. However, it is yet unclear whether other talkers’ global rates are encoded with reference to a listener’s self-produced rate. Three experiments addressed this question. In Experiment 1, one group of participants was instructed to speak fast, whereas another group had to speak slowly. The groups were compared on their perception of ambiguous /α/-/a:/ vowels embedded in neutral rate speech from another talker. In Experiment 2, the same participants listened to playback of their own speech and again evaluated target vowels in neutral rate speech. Neither of these experiments provided support for the involvement of self-produced speech in perception of another talker’s speech rate. Experiment 3 repeated Experiment 2 but with a new participant sample that was unfamiliar with the participants from Experiment 2. This experiment revealed fewer /a:/ responses in neutral speech in the group also listening to a fast rate, suggesting that neutral speech sounds slow in the presence of a fast talker and vice versa. Taken together, the findings show that self-produced speech is processed differently from speech produced by others. They carry implications for our understanding of rate-dependent speech perception in dialogue settings, suggesting that both perceptual and cognitive mechanisms are involved.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 5
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-06
    Description: by Jill A. McDonald, Anup Amatya, Charlotte C. Gard, Jesus Sigala Background Cesarean delivery occurs in one in three US births and poses risks for mothers and infants. Hispanic cesarean rates were higher than non-Hispanic white rates in the US in 2016. In 2009, cesarean rates among Hispanics on the US-Mexico border exceeded rates among US Hispanics. Since 2009, rates have declined nationwide, but border Hispanic rates have not been studied. Objective To compare cesarean delivery rates and trends in Hispanics and non-Hispanic whites in border and nonborder counties of the four US border states before and after 2009. Study Design We used data from birth certificates to calculate percentages of cesarean deliveries among all births and births to low-risk nulliparous women during 2000–2015, and among births to low-risk women with and without a previous cesarean during 2009–2015. We calculated 95% confidence intervals around rates and used regular and piecewise linear regression to estimate trends for four ethnic-geographic subpopulations defined by combinations of Hispanic ethnicity and border-nonborder status. Results Of the four subpopulations, border Hispanic rates were highest every year for all cesarean outcomes. In 2015 they were 38.3% overall, 31.4% among low-risk nulliparous women, and 21.1% and 94.6% among low-risk women without and with a previous cesarean, respectively. Nonborder Hispanic rates in 2015 were lowest for all outcomes but repeat cesarean. Rates for all four subpopulations rose steadily during 2000–2009. Unlike rates for non-Hispanic whites, border and nonborder Hispanic rates did not decline post-2009. Most of the border Hispanic excess can be attributed to higher cesarean rates in Texas. Discussion Border Hispanic cesarean rates remain higher than those among other Hispanics and non-Hispanic whites in border states and show no signs of declining. This continuing disparity warrants further analysis using individual as well as hospital, environmental and other contextual factors to help target prevention measures.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 6
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Itamar Eliakim, Zahi Cohen, Gabor Kosa, Yossi Yovel Echolocating bats rely on active sound emission (echolocation) for mapping novel environments and navigating through them. Many theoretical frameworks have been suggested to explain how they do so, but few attempts have been made to build an actual robot that mimics their abilities. Here, we present the ‘Robat’—a fully autonomous bat-like terrestrial robot that relies on echolocation to move through a novel environment while mapping it solely based on sound. Using the echoes reflected from the environment, the Robat delineates the borders of objects it encounters, and classifies them using an artificial neural-network, thus creating a rich map of its environment. Unlike most previous attempts to apply sonar in robotics, we focus on a biological bat-like approach, which relies on a single emitter and two ears, and we apply a biological plausible signal processing approach to extract information about objects’ position and identity.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 7
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Imke Spöring, Vincent A. Martinez, Christian Hotz, Jana Schwarz-Linek, Keara L. Grady, Josué M. Nava-Sedeño, Teun Vissers, Hanna M. Singer, Manfred Rohde, Carole Bourquin, Haralampos Hatzikirou, Wilson C. K. Poon, Yann S. Dufour, Marc Erhardt Most bacteria swim in liquid environments by rotating one or several flagella. The long external filament of the flagellum is connected to a membrane-embedded basal body by a flexible universal joint, the hook, which allows the transmission of motor torque to the filament. The length of the hook is controlled on a nanometer scale by a sophisticated molecular ruler mechanism. However, why its length is stringently controlled has remained elusive. We engineered and studied a diverse set of hook-length variants of Salmonella enterica . Measurements of plate-assay motility, single-cell swimming speed, and directional persistence in quasi-2D and population-averaged swimming speed and body angular velocity in 3D revealed that the motility performance is optimal around the wild-type hook length. We conclude that too-short hooks may be too stiff to function as a junction and too-long hooks may buckle and create instability in the flagellar bundle. Accordingly, peritrichously flagellated bacteria move most efficiently as the distance travelled per body rotation is maximal and body wobbling is minimized. Thus, our results suggest that the molecular ruler mechanism evolved to control flagellar hook growth to the optimal length consistent with efficient bundle formation. The hook-length control mechanism is therefore a prime example of how bacteria evolved elegant but robust mechanisms to maximize their fitness under specific environmental constraints.
    Print ISSN: 1544-9173
    Electronic ISSN: 1545-7885
    Topics: Biology
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  • 8
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Helmut Schmidt, Daniele Avitabile, Ernest Montbrió, Alex Roxin Oscillatory activity robustly correlates with task demands during many cognitive tasks. However, not only are the network mechanisms underlying the generation of these rhythms poorly understood, but it is also still unknown to what extent they may play a functional role, as opposed to being a mere epiphenomenon. Here we study the mechanisms underlying the influence of oscillatory drive on network dynamics related to cognitive processing in simple working memory (WM), and memory recall tasks. Specifically, we investigate how the frequency of oscillatory input interacts with the intrinsic dynamics in networks of recurrently coupled spiking neurons to cause changes of state: the neuronal correlates of the corresponding cognitive process. We find that slow oscillations, in the delta and theta band, are effective in activating network states associated with memory recall. On the other hand, faster oscillations, in the beta range, can serve to clear memory states by resonantly driving transient bouts of spike synchrony which destabilize the activity. We leverage a recently derived set of exact mean-field equations for networks of quadratic integrate-and-fire neurons to systematically study the bifurcation structure in the periodically forced spiking network. Interestingly, we find that the oscillatory signals which are most effective in allowing flexible switching between network states are not smooth, pure sinusoids, but rather burst-like, with a sharp onset. We show that such periodic bursts themselves readily arise spontaneously in networks of excitatory and inhibitory neurons, and that the burst frequency can be tuned via changes in tonic drive. Finally, we show that oscillations in the gamma range can actually stabilize WM states which otherwise would not persist.
    Print ISSN: 1553-734X
    Electronic ISSN: 1553-7358
    Topics: Biology , Computer Science
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  • 9
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Weizhong Chen, Yi Liu, Shanshan Zhu, Guoyu Chen, Jing-Dong J. Han Combinatorial effects of epigenetic modifications on transcription activity have been proposed as “histone codes”. However, it is unclear whether there also exist inter-nucleosomal communications among epigenetic modifications at single nucleosome level, and if so, what functional roles they play. Meanwhile, how clear nucleosome patterns, such as nucleosome phasing and depletion, are formed at functional regions remains an intriguing enigma. To address these questions, we developed a Bayesian network model for interactions among different histone modifications across neighboring nucleosomes, based on the framework of dynamic Bayesian network (DBN). From this model, we found that robust inter-nucleosomal interactions exist around transcription start site (TSS), transcription termination sites (TTS) or around CTCF binding sites; and these inter-nucleosomal interactions are often involved in transcription regulation. In addition to these general principles, DBN also uncovered a novel specific epigenetic interaction between H2A.Z and H4K20me1 on neighboring nucleosomes, involved in nucleosome free region (NFR) and nucleosome phasing establishment or maintenance. The level of negative correlation between neighboring H2A.Z and H4K20me1 strongly correlate with the size of NFR and the strength of nucleosome phasing around TSS. Our study revealed inter-nucleosomal communications as important players in signal propagation, chromatin remodeling and transcription regulation.
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  • 10
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Ankur Garg, Abdul Hannan, Qian Wang, Tamica Collins, Siying Teng, Mukesh Bansal, Jian Zhong, Keli Xu, Xin Zhang FGF signaling is a potent inducer of lacrimal gland development in the eye, capable of transforming the corneal epithelium into glandular tissues. Here, we show that genetic ablation of the Pea3 family of transcription factors not only disrupted the ductal elongation and branching of the lacrimal gland, but also biased the lacrimal gland epithelium toward an epidermal cell fate. Analysis of high-throughput gene expression and chromatin immunoprecipitation data revealed that the Pea3 genes directly control both the positive and negative feedback loops of FGF signaling. Importantly, Pea3 genes are also required to suppress aberrant Notch signaling which, if gone unchecked, can compromise lacrimal gland development by preventing the expression of both Sox and Six family genes. These results demonstrate that Pea3 genes are key FGF early response transcriptional factors, programing the genetic landscape for cell fate determination.
    Print ISSN: 1553-7390
    Electronic ISSN: 1553-7404
    Topics: Biology
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  • 11
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Choongwon Jeong, David B. Witonsky, Buddha Basnyat, Maniraj Neupane, Cynthia M. Beall, Geoff Childs, Sienna R. Craig, John Novembre, Anna Di Rienzo Adaptive evolution in humans has rarely been characterized for its whole set of components, i.e. selective pressure, adaptive phenotype, beneficial alleles and realized fitness differential. We combined approaches for detecting polygenic adaptations and for mapping the genetic bases of physiological and fertility phenotypes in approximately 1000 indigenous ethnically Tibetan women from Nepal, adapted to high altitude. The results of genome-wide association analyses and tests for polygenic adaptations showed evidence of positive selection for alleles associated with more pregnancies and live births and evidence of negative selection for those associated with higher offspring mortality. Lower hemoglobin level did not show clear evidence for polygenic adaptation, despite its strong association with an EPAS1 haplotype carrying selective sweep signals.
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  • 12
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Jennifer K. Pleiman, Amy A. Irving, Zhishi Wang, Erik Toraason, Linda Clipson, William F. Dove, Dustin A. Deming, Michael A. Newton Conservation over three mammalian genera—the mouse, rat, and human—has been found for a subset of the transcripts whose level differs between the adenoma and normal epithelium of the colon. Pde4b is one of the triply conserved transcripts whose level is enhanced both in the colonic adenoma and in the normal colonic epithelium, especially adjacent to adenomas. It encodes the phosphodiesterase PDE4B, specific for cAMP. Loss of PDE4B function in the Apc Min/+ mouse leads to a significant increase in the number of colonic adenomas. Similarly, Pde4b -deficient Apc Min/+ mice are hypersensitive to treatment by the inflammatory agent DSS, becoming moribund soon after treatment. These observations imply that the PDE4B function protects against Apc Min -induced adenomagenesis and inflammatory lethality. The paradoxical enhancement of the Pde4b transcript in the adenoma versus this inferred protective function of PDE4B can be rationalized by a feedback model in which PDE4B is first activated by early oncogenic stress involving cAMP and then, as reported for frank human colon cancer, inactivated by epigenetic silencing.
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  • 13
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Kärt Tomberg, Randal J. Westrick, Emilee N. Kotnik, Audrey C. Cleuren, David R Siemieniak, Guojing Zhu, Thomas L. Saunders, David Ginsburg Although the Factor V Leiden (FVL) gene variant is the most prevalent genetic risk factor for venous thrombosis, only 10% of FVL carriers will experience such an event in their lifetime. To identify potential FVL modifier genes contributing to this incomplete penetrance, we took advantage of a perinatal synthetic lethal thrombosis phenotype in mice homozygous for FVL ( F5 L/L ) and haploinsufficient for tissue factor pathway inhibitor ( Tfpi +/- ) to perform a sensitized dominant ENU mutagenesis screen. Linkage analysis conducted in the 3 largest pedigrees generated from the surviving F5 L/L Tfpi +/- mice (‘rescues’) using ENU-induced coding variants as genetic markers was unsuccessful in identifying major suppressor loci. Whole exome sequencing was applied to DNA from 107 rescue mice to identify candidate genes enriched for ENU mutations. A total of 3,481 potentially deleterious candidate ENU variants were identified in 2,984 genes. After correcting for gene size and multiple testing, Arl6ip5 was identified as the most enriched gene, though not reaching genome-wide significance. Evaluation of CRISPR/Cas9 induced loss of function in the top 6 genes failed to demonstrate a clear rescue phenotype. However, a maternally inherited (not ENU-induced) de novo mutation ( Plcb4 R335Q ) exhibited significant co-segregation with the rescue phenotype (p = 0.003) in the corresponding pedigree. Thrombosis suppression by heterozygous Plcb4 loss of function was confirmed through analysis of an independent, CRISPR/Cas9-induced Plcb4 mutation (p = 0.01).
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  • 14
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    Publication Date: 2018-09-07
    Description: by Jillian S. Gauld, Hao Hu, Daniel Klein, Myron M. Levine Typhoid fever is endemic in many developing countries. In the early 20 th century, newly industrializing countries including the United States successfully controlled typhoid as water treatment (chlorination/sand filtration) and improved sanitation became widespread. Enigmatically, typhoid remained endemic through the 1980s in Santiago, Chile, despite potable municipal water and widespread household sanitation. Data were collected across multiple stages of endemicity and control in Santiago, offering a unique resource for gaining insight into drivers of transmission in modern settings. We developed an individual-based mathematical model of typhoid transmission, with model components including distinctions between long-cycle and short-cycle transmission routes. Data used to fit the model included the prevalence of chronic carriers, seasonality, longitudinal incidence, and age-specific distributions of typhoid infection and disease. Our model captured the dynamics seen in Santiago across endemicity, vaccination, and environmental control. Both vaccination and diminished exposure to seasonal amplified long-cycle transmission contributed to the observed declines in typhoid incidence, with the vaccine estimated to elicit herd effects. Vaccines are important tools for controlling endemic typhoid, with even limited coverage eliciting herd effects in this setting. Removing the vehicles responsible for amplified long-cycle transmission and assessing the role of chronic carriers in endemic settings are additional key elements in designing programs to achieve accelerated control of endemic typhoid.
    Print ISSN: 1935-2727
    Electronic ISSN: 1935-2735
    Topics: Medicine
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  • 15
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by William P. D. Hendricks, Victoria Zismann, Karthigayini Sivaprakasam, Christophe Legendre, Kelsey Poorman, Waibhav Tembe, Nieves Perdigones, Jeffrey Kiefer, Winnie Liang, Valerie DeLuca, Mitchell Stark, Alison Ruhe, Roe Froman, Nicholas S. Duesbery, Megan Washington, Jessica Aldrich, Mark W. Neff, Matthew J. Huentelman, Nicholas Hayward, Kevin Brown, Douglas Thamm, Gerald Post, Chand Khanna, Barbara Davis, Matthew Breen, Alexander Sekulic, Jeffrey M. Trent Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.
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  • 16
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Pornpan Suntornsut, Wipada Chaowagul, Wilasinee Thongklang, Thidarat Phosri, Nicholas P. J. Day, Susan Michie, Direk Limmathurotsakul Background Melioidosis is an infection caused by Burkholderia pseudomallei , a Gram-negative bacillus found in soil and water. Diabetes mellitus is the most important risk factor for melioidosis. The recommendations for disease prevention include avoiding direct contact with soil and water, and drinking only boiled or bottled water. Methods A prospective intervention study was conducted to evaluate the feasibility and behavioural outcomes of a multifaceted prevention programme for melioidosis. Participants were diabetic adults in Ubon Ratchathani, northeast Thailand. Ten behavioural support groups consisting of 6 to 10 participants per group were conducted. Twelve behaviour change techniques were used: information about health consequences, credible source, adding objects to the environment, reconstructing the physical environment, instruction on how to perform a behaviour, demonstration of the behaviour, commitment, prompts/cues, self-monitoring of behaviour, goal setting, feedback on behaviour, and social support, and their feasibilities evaluated. Results There were 70 participants, of median age 59 years and 52 (74%) were female. Participants found the intervention beneficial, interesting and engaging. Participants indicated that they liked to watch videos with information about melioidosis delivered by local doctors and patients who survived melioidosis, and videos showing use of over-the-knee boots by local farmers. Participants felt engaged in the sessions that trialed protective gear and that made calendars with individual photographs and self-pledges as a reminder tool. The proportions of participants reporting that they always wore boots while working in rice fields increased from 30% (10/33) to 77% (28/37, p = 0.04), and that they drank only boiled or bottle water increased from 43% (30/70) to 86% (59/69, p
    Print ISSN: 1935-2727
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  • 17
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    Publication Date: 2018-09-07
    Description: by Ana Hernández-González, Carlos Sánchez-Ovejero, Raúl Manzano-Román, María González Sánchez, José Manuel Delgado, Teresa Pardo-García, Francisco Soriano-Gálvez, Okan Akhan, Carmen M. Cretu, Kamenna Vutova, Francesca Tamarozzi, Mara Mariconti, Enrico Brunetti, Ambra Vola, Massimo Fabiani, Adriano Casulli, Mar Siles-Lucas Cystic echinococcosis (CE) is one of the most widespread helminthic zoonoses and is caused by the tapeworm Echinococcus granulosus complex. CE diagnosis and monitoring primarily rely on imaging techniques, complemented by serology. This is usually approached by the detection of IgG antibodies against hydatid fluid (HF), but the use of this heterogeneous antigenic mixture results in a variable percentage of false positive and negative results, and has shown to be useless for follow-up due to the long persistence of anti-HF antibodies in cured patients. To improve test performances and standardization, a number of recombinant antigens mainly derived from HF have been described, among them the B2t and 2B2t antigens. The performance of these antigens in the diagnosis and follow up of patients with CE has been so far evaluated on a limited number of samples. Here, we evaluated the performances of tests based on B2t and 2B2t recombinant antigens compared to HF in IgG-ELISA and immunochromatography (IC) for the diagnosis and follow-up of patients with CE in a retrospective cohort study. A total of 721 serum samples were collected: 587 from 253 patients with CE diagnosed by ultrasonography (US), 42 from patients with alveolar echinococcosis and 92 from healthy donors from Salamanca (Spain). The highest overall sensitivity was obtained with HF in ELISA (85.5%), followed by IC containing HF and 2B2t-HF (83.0% and 78.2%, respectively). The lowest sensitivity was obtained with B2t and 2B2t in ELISA (51.8%). The highest specificity was obtained with IC containing 2B2t-HF (100%), and the lowest with HF-ELISA (78.0%). The lowest cross-reactivity with sera from patients with alveolar echinococcosis was detected with the recombinant antigens in ELISA (9.5% - 16.7%) and the highest with the HF-IC (64.3%). The results of B2t and 2B2t-ELISA were influenced by cyst stage, as classified by US according to the WHO-Informal Working Group on Echinococcosis (WHO-IWGE), with low sensitivity for inactive (CE4 and CE5) cysts, and by the drug treatment, with higher sensitivity in patients after drug treatment compared with patients not subjected to drug treatment. The two recombinant antigens in ELISA provided promising results for monitoring patients in follow-up, although their use is limited to patients with positive serology against them at the beginning of the follow-up. Potential biological reasons behind the low sensitivity of the recombinant antigens and possible strategies to enhance the performance of CE serology are discussed.
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  • 18
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    Publication Date: 2018-09-07
    Description: by Camila H. Coelho, Steven M. Singer
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  • 19
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    Publication Date: 2018-09-07
    Description: by Chen Chen, Dong Jiang, Ming Ni, Jing Li, Zhihai Chen, Jingyuan Liu, Hanhui Ye, Gary Wong, Wei Li, Yuanyuan Zhang, Beibei Wang, Yuhai Bi, Danying Chen, Ping Zhang, Xuesen Zhao, Yaxian Kong, Weifeng Shi, Pengcheng Du, Gengfu Xiao, Juncai Ma, George F. Gao, Jie Cui, Fujie Zhang, Wenjun Liu, Xiaochen Bo, Ang Li, Hui Zeng, Di Liu The yellow fever virus (YFV) recently reemerged in the large outbreaks in Africa and Brazil, and the first imported patients into Asia have recalled the concerns of YFV evolution. Here we show phylogenomics of YFV with serial clinical samples of the 2016 YFV infections. Phylogenetics exhibited that the 2016 strains were close to Angola 1971 strains and only three amino acid changes presented new to other lineages. Deep sequencing of viral genomes discovered 101 intrahost single nucleotide variations (iSNVs) and 234 single nucleotide polymorphisms (SNPs). Analysis of iSNV distribution and mutated allele frequency revealed that the coding regions were under purifying selection. Comparison of the evolutionary rates estimated by iSNV and SNP showed that the intrahost rate was ~2.25 times higher than the epidemic rate, and both rates were higher than the long-term YFV substitution rate, as expected. In addition, the result also hinted that short viremia duration of YFV might further hinder the evolution of YFV.
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  • 20
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    Publication Date: 2018-09-07
    Description: by Anaïs Broban, Mathurin C. Tejiokem, Issaka Tiembré, Sophie Druelles, Maïna L’Azou
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  • 21
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Juliana Maria Trindade Bezerra, Valdelaine Etelvina Miranda de Araújo, David Soeiro Barbosa, Francisco Rogerlândio Martins-Melo, Guilherme Loureiro Werneck, Mariângela Carneiro Background The study presents estimates for the burden of visceral leishmaniasis (VL) and cutaneous and mucocutaneous leishmaniasis (CML) in Brazil and its 27 federated units using data from the Global Burden of Disease Study (GBD) 2016. Methodology We report the incidence, years of life lost (YLL), years lived with disability (YLD), and disability-adjusted life years (DALY) for leishmaniasis in Brazil from 1990 to 2016. The metrics are presented as age-standardized rates per 100,000 inhabitants with their respective uncertainty intervals (95%UI) and relative percentages of change. Principal findings The age-standardized incidence rate of leishmaniasis decreased 48.5% from 1990 (71.0, 95%UI 24.3–150.7) to 2016 (36.5, 95%UI 24.7–50.9), whereas the age-standardized DALY increased 83.6% over the studied period from 12.2 (95%UI 7.9–18.8) to 22.4 (95%UI 13.3–36.2). The age-standardized incidence rate and YLL for VL increased by 52.9% and 108% from 1990 to 2016, respectively. Considering CML, the age-standardized incidence rate and YLD decreased by 51% and 31.8% respectively for the same period. For VL, similar profiles for male and female were observed, with YLL and DALY increasing over time; with males presenting slightly higher values. The highest YLL rates were among "under 1-year old" children, which increased 131.2% from 1990 to 2016. Regarding CML, the highest values of YLD and DALY were verified among males, and YLD values showed a similar profile, with rates increasing with age. The VL burden increased in some states in the Northeast and Southeast regions and decreased for CML in some Northern states. Conclusion The increase of VL burden over the study period might be associated with the difficulties in controlling the disease spread. Information regarding the weight of VL and CML, including the death and disability tolls that they cause, highlights the impact of these neglected diseases on public health and the importance of effective prevention and treatment.
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    Publication Date: 2018-09-07
    Description: by Issaka Tiembré, Anaïs Broban, Joseph Bénié, Mathilde Tetchi, Sophie Druelles, Maïna L’Azou In Côte d’Ivoire, rabies is endemic and remains largely uncontrolled. The numbers of human exposures and rabies cases are unknown and are probably much higher than reported. Data on human rabies cases are collected by the National Institute of Public Health (NIPH) Anti-rabies Center in Abidjan through a network of 28 NIPH local units, which cover the population of the entire country. During 2014, the NIPH initiated a program to reinforce the human rabies surveillance system in those 28 NIPH local units, with specific goals of improving the infrastructure, training, communication, and government involvement. Here, we report the progress and findings during 2014–2016. The reinforced system recorded 50 cases of human rabies (15–18 cases/year; annual incidence = 0.06−0.08 per 100,000) and more than 30,000 animal exposures (annual incidence = 41.8−48.0 per 100,000). Almost one-half of the human rabies cases were in children ≤15 years old. All were fatal and dog bites were the most common route by which rabies virus was transmitted. In the 32 cases where samples of sufficient quality for analysis were available, rabies was confirmed by reverse transcription-polymerase chain reaction RT-PCR. Post-exposure prophylaxis with rabies vaccine was administered to all animal exposure victims presenting at the NIPH local units, although only about 57% completed the full immunization schedule. All available reports were provided by the NIPH local units, indicating effective communication between them and the NIPH Anti-rabies Center. These findings indicate that the reinforcements resulted in highly specific detection of human rabies, provided detailed epidemiological data about these cases, and improved estimates of animal exposure numbers. These represent substantial advances, but further improvements to the surveillance system are needed to increase disease awareness and capture cases that are currently missed by the system. In the future, better communication between local health centers and the NIPH units, surveillance at the local health center level, and increased veterinarian engagement will help provide a more complete picture of the rabies burden in Côte d’Ivoire.
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  • 23
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 24
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    Publication Date: 2018-09-07
    Description: by Casimir Ledoux Sofeu, Anaïs Broban, Amadou Njifou Njimah, Jean Blaise Momo, Serge Alain Sadeuh-Mba, Sophie Druelles, Maïna L’Azou, Mathurin Cyrille Tejiokem Canine rabies is endemic in Cameroon, but human rabies exposures and cases are likely underreported because of inadequate surveillance. In 2014, the surveillance network in the West region of Cameroon was reinforced by introducing a new anti-rabies center, a framework for data collection and evaluation, provisions for sample collecting and laboratory confirmation, and training for health professionals. The objective of this observational cohort study was to describe the incidence and characteristics of reported exposures and human and animal rabies cases following this reinforcement of the existing rabies surveillance system. The surveillance network consisted of local, regional, and national health and veterinary authorities in 11 of the 20 West region districts, and was completely integrated within the existing national rabies surveillance network. Animal exposures and suspected rabies exposures, the suspected rabid animals involved, and laboratory confirmation of human and animal rabies cases were recorded in a centralized information database. Between January 2014 and June 2016, the network recorded 1340 animal exposure cases for an overall incidence rate of 38.2 animal exposures per 100,000 people, four confirmed rabies-positive animals, and one confirmed human rabies case out of four clinically suspected cases. In contrast, 62 animal exposures and an overall incidence rate of 6.1 exposures per 100,000 people were reported for the West region districts not participating in the reinforced surveillance. Of the 925 animal exposure victims for whom a detailed case report form was completed, 703 were considered to be at risk of rabies and only 428 (61%) of these received any post-exposure prophylaxis in the form of rabies vaccine. Obstacles encountered within the network included low rates of animal sample submission and animal follow-up by veterinarians. Reinforced rabies surveillance in the West region of Cameroon has provided the most accurate estimate of the region’s disease and exposure burdens to date, and indicates that animal exposures are substantially underreported. The reinforced network also signaled that greater access to post-exposure prophylaxis is needed. Integration of regions not covered by the surveillance network and efforts to improve engagement of veterinary services will be needed to reveal the true burden of rabies in Cameroon.
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  • 25
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    Publication Date: 2018-09-07
    Description: by Manjit Bista, Saroj Panthi, Sarah R. Weiskopf Studying habitat overlap between sympatric species is one of the best ways to identify interspecies relationships and to direct conservation efforts so that multiple species can benefit. However, studies exploring interspecies relationships are very limited in Nepal, making it difficult for the government of Nepal and conservation partners to manage wildlife in their habitats, especially in Himalayan protected areas. In this study, we identified habitat overlap between Asiatic black bear ( Ursus thibetanus ) and red panda ( Ailurus fulgens ) as well as important habitat types for both species in the Makalu Barun National Park, Nepal using Maximum Entropy (MaxEnt) modeling. GPS points of species occurrence were collected from the field, and environmental variables were extracted from freely available sources. We found that the study area contained 647 km 2 of Asiatic black bear habitat and 443 km 2 of the red panda habitat. 368 km 2 supported both species, which constituted 57% of the Asiatic black bear habitat and 83% of the red panda habitat. We found that conifer forest was the most important habitat type for both species. Because the largest portions of both species’ habitat were located inside the buffer zone, a peripheral zone of national park, conservation efforts for these sympatric species should be focused inside the buffer zone to be most effective.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-09-07
    Description: by Agathe Leblond, Sonia Pezet, Anne Priscille Trouvin, Muriel Elhai, Virginie Gonzalez, Yannick Allanore, Jérôme Avouac Background Neoangiogenesis is a crucial event to promote the development of the hyperplasic proliferative pathologic synovium in Rheumatoid arthritis (RA). Ultrasound (US) is sensitive for detection of power Doppler (PD) vascularization. Objective To explore the associations between a set of complementary circulating angiogenic markers and a comprehensive US assessment in patients with RA. Patients and methods Serum levels of eight angiogenic markers were measured by quantitative ELISAs in a total of 125 patients with RA, who were all systematically assessed in parallel by PDUS, performed on 32 joints. Results Serum levels of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and Tie-2 were more likely to be increased in patients with synovial hyperemia detected on at least one joint (Power Doppler grade ≥1). sVCAM-1, Tie-2 and Angiostatin concentrations gradually increased together with the grade of the semiquantitative PDUS scale and concentrations of these three markers were markedly increased in patients with moderate to marked hyperemia (Power Doppler grade 2 and 3). Levels of sVCAM-1, Tie-2, and Angiostatin correlated with a global arthritis sum score, defined by the sum of the semiquantitative PDUS scores for all joints examined. Levels of Tie-2 and Placenta Growth Factor (PlGF) were associated with PDUS features indicating residual disease activity. Conclusion Our results support the relevance of measuring serum levels of vascular markers to evaluate the intensity and extent of synovial vascularization. Angiogenic markers, and particularly Tie-2, could be a valuable surrogate of active synovitis and their place in relation to PDUS in clinical practice deserve further investigation.
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    Publication Date: 2018-09-07
    Description: by Abdullah Nurus Salam Khan, Sk Masum Billah, Ishtiaq Mannan, Imteaz Ibne Mannan, Tahmina Begum, Marufa Aziz Khan, Munia Islam, S. M. Monirul Ahasan, Jebun Nessa Rahman, Joby George, Shams El Arifeen, Umme Salma Jahan Meena, Iftekhar Rashid, Joseph de Graft-Johnson Background In Bangladesh, female paramedics known as Family Welfare Visitors (FWVs), conduct normal deliveries in first-level primary care facilities, or Union Health and Family Welfare Centres (UH&FWC). Utilization of partographs allow for early identification of abnormal labour and referral for advanced care to Emergency Obstetric Care (EmOC) facilities. A systematic assessment of the quality of partograph utilization in clinical-decision making will contribute to understanding the use of the tool by health workers. Methods In 2013, the USAID supported MaMoni HSS project, led in country by Save the Children, trained FWVs on the use of partographs in five UH&FWCs in Habiganj district. As part of the follow-up after training, intrapartum case record forms, accompanying partographs, and referral registers for all obstetric cases managed in these five facilities from July 2013 to June 2014 were reviewed. Partographs were reviewed to identify abnormal labour cases based on pre-defined indications. All referred cases were ascertained from the case records in the referral registers. Five health workers were interviewed to assess their knowledge, attitude and experience in partograph use and to explore the challenges for referral decision making associated with the tool. Results A total of 1,198 deliveries were managed at the study sites, of which 663 presented with cervical dilatation of 8 cm or less. Partographs were initiated in 98% of these cases. Indication of abnormal labour was found in 71 partographs (11%) and among them, only 1 was referred to a higher-level facility. Foetal heart rate and cervical dilatation were appropriately recorded in 61% and 70% of the partographs, respectively. Interviews with health workers revealed poor interpretation of referral indications from the partographs. Limited accessibility to the nearest EmOC facility, inadequate time for referral, and non-compliance to referral by clients were identified by the interviewed health workers as the key barriers for referral decision making. Conclusions Supporting the health workers at first-level primary care facilities to better interpret and act on partograph data in a timely manner, and strengthening the referral systems are needed to ensure that women in labour receive the prompt quality care they and their babies require to survive.
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  • 28
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    Publication Date: 2018-09-07
    Description: by André Hajek, Hans-Helmut König Background The aim of this study was to identify whether informal caregiving time is associated with personality factors longitudinally. Methods Longitudinal data were gathered from the German Socio-Economic Panel (GSOEP), a large nationally representative, longitudinal study of German households beginning in 1984. Focusing on the association between informal caregiving and personality factors, data were used from the years 2005, 2009 and 2013. The GSOEP Big Five Inventory was used to assess personality factors. Informal caregiving hours were used as explanatory variable. The explanatory variable informal caregiving hours was categorized into 0 hours (reference), 1 hours, 2 hours, 3 hours, 4 hours, and 5 hours and more. Age, marital status, educational level, employment status, income, self-rated health and disability were included as potential confounders in regression analysis. Results Adjusting for potential confounders, fixed effects regressions showed that whether or not someone provides informal care is markedly associated with changes in neuroticism. Given that an individual provides informal care, the actual number of care hours did not matter in most cases. Informal caregiving was not associated with openness to experience, extraversion and agreeableness. As regards conscientiousness, only ‘5 hours and more’ on a typical Sunday was associated with an increase in conscientiousness (β = .32, p 〈 .05). Informal caregiving on a typical weekday or Saturday was not associated with changes in conscientiousness. Conclusion Our findings stress the longitudinal association between informal caregiving and neuroticism.
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    Publication Date: 2018-09-07
    Description: by Melissa Davidsen Jørstad, Jörg Aẞmus, Msafiri Marijani, Lisbet Sviland, Tehmina Mustafa Background Early and proper treatment of tuberculosis could have an important impact on the morbidity, mortality and the economic situation of patients. There is insufficient knowledge on the extent of diagnostic delay and the associated factors in extrapulmonary tuberculosis (EPTB). The aims of this study were to assess the health care seeking behaviour, EPTB knowledge and diagnostic delay in presumptive EPTB patients at the main referral hospital in Zanzibar, factors associated with longer delay, and the impact of untreated EPTB on self-rated health. Materials and methods Prospective data collection using a semi-structured questionnaire in patients presenting with symptoms suggestive of EPTB. The time between the onset of symptoms and first visit to a health care provider (patient delay), and then to the initiation of treatment (health system delay) and total delay were analysed according to sociodemographic and clinical factors and health care seeking trajectories. The EQ-5D-3L was used among the adult EPTB patients to assess the impact of treatment on self-rated health. Results Of the 132 patients with median age of 27 years (interquartile range 8–41), 69 were categorized as TB cases and 63 as non-TB cases. The median patient, health system and total delays were 14, 34 and 62 days respectively, among the EPTB patients. A longer health system delay with repeated visits to the same health care level was reported. Significantly better self-rated health status was described after treatment. The knowledge regarding extrapulmonary disease was low. Conclusion Many EPTB patients, presenting to the main referral hospital in Zanzibar, experience a long delay in the initiation of treatment, specially patients with TB lymphadenitis. The health system delay is the major contributor to the total delay. The improvement of self-rated health after treatment implies that timely treatment has the potential to reduce morbidity and the economic loss for the patient.
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    Publication Date: 2018-09-07
    Description: by Sarah A. Skubel, Vyacheslav Dushenkov, Brittany L. Graf, Qingwei Niu, Alexander Poulev, Hetalben M. Kalariya, Llewellyn C. Foxcroft, Ilya Raskin Study of plant metabolome is a growing field of science that catalogs vast biochemical and functional diversity of phytochemicals. However, collecting and storing samples of plant metabolome, sharing these samples across the scientific community and making them compatible with bioactivity assays presents significant challenges to the advancement of metabolome research. We have developed a RApid Metabolome Extraction and Storage (RAMES) technology that allows efficient, highly compact, field-deployable collection and storage of libraries of plant metabolome. RAMES technology combines rapid extraction with immobilization of extracts on glass microfiber filter discs. Two grams of plant tissue extracted in ethanol, using a specially adapted Dremel ® rotary tool, produces 25–35 replicas of 10 mm glass fiber discs impregnated with phytochemicals. These discs can be either eluted with solvents (such as 70% ethanol) to study the metabolomic profiles or used directly in a variety of functional assays. We have developed simple, non-sterile, anti-fungal, anti-bacterial, and anti-oxidant assays formatted for 24-multiwell plates directly compatible with RAMES discs placed inside the wells. Using these methods we confirmed activity in 30 out of 32 randomly selected anti-microbial medicinal plants and spices. Seven species scored the highest activity (total kill) in the anti-bacterial (bacteria from human saliva) and two anti-fungal screens ( Fusarium spp. and Saccharomyces cerevisiae ), providing functional validation of RAMES technology. RAMES libraries showed limited degradation of compounds after 12 months of storage at -20°C, while others remained stable. Fifty-eight percent of structures characterized in the extracts loaded onto RAMES discs could be eluted from the discs without significant losses. Miniaturized RAMES technology, as described and validated in this manuscript offers a labor, cost, and time-effective alternative to conventional collection of phytochemicals. RAMES technology enables creation of comprehensive metabolomic libraries from various ecosystems and geographical regions in a format compatible with further biochemical and functional studies.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-09-07
    Description: by Christian Rassi, Georgia R. Gore-Langton, Badru Gidudu Walimbwa, Clare E. Strachan, Rebecca King, Sinwan Basharat, Celine Christiansen-Jucht, Kirstie Graham, Sam Siduda Gudoi Poor health worker performance is a well-documented obstacle to quality service provision. Due to the increasingly widespread availability of mobile devices, mobile health (mHealth) has received growing attention as a service improvement tool. This pilot study explored feasibility, acceptability and outcomes of an mHealth intervention designed to increase coverage of intermittent preventive treatment of malaria in pregnancy (IPTp) in two districts of West Nile, Uganda. In both districts, selected health workers (N = 48) received classroom training on malaria in pregnancy. All health workers in one district (N = 49) subsequently received 24 text messages reinforcing the training content. The intervention was evaluated using a mixed-methods approach, including four focus group discussions with health workers and three in-depth interviews with district health officials, health worker knowledge assessments one month (N = 90) and six months (N = 89) after the classroom training, and calculation of IPTp coverage from participating health facilities’ (N = 16) antenatal care registers covering six months pre- and post-intervention. Complementing classroom training with text messaging was found to be a feasible, acceptable and inexpensive approach to improving health worker performance. The messages served as reminders to those who had attended the classroom training and helped spread information to those who had not. Health workers in the district where text messages were sent had significantly better knowledge of IPTp, achieving an increased composite knowledge score of 6.00 points (maximum score: 40) compared with those in the district where only classroom training was provided. Average facility coverage of three doses of IPTp was also significantly higher where text messages were sent (85.8%) compared with the district where only classroom training was provided (54.1%). This intervention shows promise for the improvement of health worker performance for delivery of IPTp, and could have significant broader application.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-09-07
    Description: by Yuiko Sakuta, So Kanazawa, Masami K. Yamaguchi Recently, various studies have clarified that humans can immediately make social evaluations from facial appearance and that such judgment have an important role in several social contexts. However, the origins and early development of this skill have not been well investigated. To clarify the mechanisms for the acquisition of this skill, we examined whether 6- to 8-month-old infants show a preference for a more trustworthy-looking person. Results showed that infants preferred a trustworthy face to an untrustworthy one when both faces were high in dominance. This difference was not seen when both faces were low in dominance. Moreover, this preference disappeared when the faces were upside down. These findings suggest that the perception of trustworthiness based on facial appearance emerges in early development with little social experience. Further research is needed to verify whether infants also perceive other traits, such as competence.
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    Publication Date: 2018-09-07
    Description: by Gemma Learmonth, Gesine Märker, Natasha McBride, Pernilla Pellinen, Monika Harvey Young adults demonstrate a small, but consistent, asymmetry of spatial attention favouring the left side of space (“pseudoneglect”) in laboratory-based tests of perception. Conversely, in more naturalistic environments, behavioural errors towards the right side of space are often observed. In the older population, spatial attention asymmetries are generally diminished, or even reversed to favour the right side of space, but much of this evidence has been gained from lab-based and/or psychophysical testing. In this study we assessed whether spatial biases can be elicited during a simulated driving task, and secondly whether these biases also shift with age, in line with standard lab-based measures. Data from 77 right-handed adults with full UK driving licences (i.e. prior experience of left-lane driving) were analysed: 38 young (mean age = 21.53) and 39 older adults (mean age = 70.38). Each participant undertook 3 tests of visuospatial attention: the landmark task, line bisection task, and a simulated lane-keeping task. We found leftward biases in young adults for the landmark and line bisection tasks, indicative of pseudoneglect, and a mean lane position towards the right of centre. In young adults the leftward landmark task biases were negatively correlated with rightward lane-keeping biases, hinting that a common property of the spatial attention networks may have influenced both tasks. As predicted, older adults showed no group-level spatial asymmetry on the landmark nor the line bisection task, but they maintained a mean rightward lane position, similar to young adults. The 3 tasks were not inter-correlated in the older group. These results suggest that spatial biases in older adults may be elicited more effectively in experiments involving complex behaviour rather than abstract, lab-based measures. More broadly, these results confirm that lateral biases of spatial attention are linked to driving behaviour, and this could prove informative in the development of future vehicle safety and driving technology.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-09-07
    Description: by Gerald Sendlhofer, David Benjamin Lumenta, Gudrun Pregartner, Karina Leitgeb, Peter Tiefenbacher, Veronika Gombotz, Christian Richter, Lars Peter Kamolz, Gernot Brunner Background The WHO Surgical Safety Checklist (SSC) was established to address important safety issues and to reduce the number of surgical deaths. So far, numerous reports have demonstrated sub-optimal implementation of the SSC in practice and limited improvements in patient outcomes. Therefore, the aim of this study was to audit the SSC-practice in a real-world setting in a university hospital setting. Methods From 2015 to 2016, independent observers performed snapshot audits in operating theatres and shadowed the three phases of the SSC. Using a 4-point Likert-scale to rate the compliance on each audit day, we generated a report highlighting possible improvements and provided feedback to the operating team members. Results Audits were performed on 36 operating days (2015: n = 19; 2016: n = 17), in which a total of 136 surgical interventions were observed. Overall, the percentage of “very good compliance” improved from 2015 to 2016: for the sign-in from 52.9% to 81.2% (p = 0.141), for the team-time-out from 33.3% to 58.8% (p = 0.181), and for the sign-out from 21.4% to 41.7% (p = 0.401). The qualitative review revealed inconsistencies when applying the SSC, of which the missing documentation of an actually performed item or the wrong timing for an item was most common. Conclusion Snapshot audits revealed that SSC compliance has improved over the observed period, while its application revealed inconsistencies during the three phases of the SSC. Snapshot audits proved to be a valuable tool in the qualitative analysis of SSC compliance and gave more insight than a mere completeness check of ticks in SSC documents.
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    Publication Date: 2018-09-07
    Description: by Juste Raimbault We study a stochastic model of urban growth generating spatial distributions of population densities at an intermediate mesoscopic scale. The model is based on the antagonist interplay between the two opposite abstract processes of aggregation (preferential attachment) and diffusion (urban sprawl). Introducing indicators to quantify urban form, the model is first statistically validated and intensively explored to understand its complex behavior across the parameter space. We then compute real morphological indicators on local areas of size 50km covering all European Union, and show that the model can reproduce most of these existing urban morphologies. It implies that the morphological dimension of urban growth processes at this scale are sufficiently captured by the two abstract processes of aggregation and diffusion.
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    Publication Date: 2018-09-07
    Description: by Elliot A. Layden, John T. Cacioppo, Stephanie Cacioppo Loneliness is thought to serve as an adaptive signal indicating the need to repair or replace salutary social connections. Accordingly, loneliness may influence preferences for interpersonal distance. If loneliness simply motivates a desire to socially reconnect, then loneliness may be associated with a preference for smaller interpersonal distances. According to the evolutionary model of loneliness, however, loneliness also signals an inadequacy of mutual aid and protection, augmenting self-preservation motives. If loneliness both increases the motivation to reconnect and increases the motivation for self-protection, then the resulting approach-avoidance conflict should produce a preference for larger interpersonal distance, at least within intimate (i.e., proximal) space. Here, we report two survey-based studies of participants’ preferences for interpersonal distance to distinguish between these competing hypotheses. In Study 1 ( N = 175), loneliness predicted preferences for larger interpersonal distance within intimate space net gender, objective social isolation, anxiety, depressive symptomatology, and marital status. In Study 2 ( N = 405), we replicated these results, and mediation analyses indicated that measures of social closeness could not adequately explain our findings. These studies provide compelling evidence that loneliness predicts preferences for larger interpersonal distance within intimate space, consistent with predictions from the evolutionary model of loneliness.
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    Publication Date: 2018-09-07
    Description: by Tsubasa S. Matsui, Hugejile Wu, Shinji Deguchi Adherent cells such as endothelial cells sense applied mechanical stretch to adapt to changes in their surrounding mechanical environment. Despite numerous studies, signaling pathways underlying the cellular mechanosensing and adaptation remain to be fully elucidated partly because of the lack of tools that allow for a comprehensive screening approach. Conventionally, multi-well cell culture plates of standard configurations are used for comprehensive analyses in cell biology study to identify key molecules in a high-throughput manner. Given that situation, here we design a 96-well cell culture plate made of elastic silicone and mechanically stretchable using a motorized device. Computational analysis suggested that highly uniform stretch can be applied to each of the wells other than the peripheral wells. Elastic image registration-based experimental evaluation on stretch distributions within individual wells revealed the presence of larger variations among wells compared to those in the computational analysis, but a stretch level of 10%–that has been employed in conventional studies on cellular response to stretch—was almost achieved with our setup. We exposed vascular smooth muscle cells to cyclic stretch using the device to demonstrate morphological repolarization of the cells, i.e. typical cellular response to cyclic stretch. Because the deformable multi-well plate validated here is compatible with other high-throughput screening-oriented technologies, we expect this novel system to be utilized for future comprehensive analyses of stretch-related signaling pathways.
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    Publication Date: 2018-09-07
    Description: by Chungwon J. Chung, Sang-Ho Cha, Amanda L. Grimm, Dharani Ajithdoss, Joanna Rzepka, Grace Chung, Jieun Yu, William C. Davis, Chak-Sum Ho Porcine reproductive and respiratory syndrome virus (PRRSV) infection is difficult to control because the virus undergoes antigenic variation during infection and also modulates the protective host immune response. Although current vaccines do not provide full protection, they have provided insight into the mechanisms of protection. Live PRRSV vaccines induce partial protection before the appearance of neutralizing antibody, suggesting cell-mediated immunity or other mechanisms may be involved. Herein, we demonstrate recovery from infection is associated with development of cytotoxic T-lymphocytes (CTL) that can kill PRRSV-infected target cells. Initial experiments showed survival of PRRSV-infected monocyte derived macrophage (MDM) targets is reduced when overlaid with peripheral blood mononuclear cells (PBMC) from gilts that had recovered from PRRSV infection. Further studies with PBMC depleted of either CD4 + or CD8 + T-cells and positively selected subpopulations of CD4 + and CD8 + T-cells showed that both CD4 + and CD8 + T-cells were involved in killing. Examination of killing at different time points revealed killing was biphasic and mediated by CTL of different phenotypes. CD4 + CD8 +high were associated with killing target cells infected for 3–6 hours. CD4 + CD8 - CTL were associated with killing at 16–24 hours. Thus, all the anti-PRRSV CTL activity in pigs was attributed to two phenotypes of CD4 + cells which is different from the anti-viral CD4 - CD8 + CTL phenotype found in most other animals. These findings will be useful for evaluating CTL responses induced by current and future vaccines, guiding to a novel direction for future vaccine development.
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    Publication Date: 2018-09-07
    Description: by Atsushi Komoto, Takayoshi Maiguma, Daisuke Teshima, Tetsuhiro Sugiyama, Yuto Haruki Objective We conducted a retrospective study based on composite endpoints for treatment failure to evaluate the effect of pharmacist-led VCM initial dose planning for Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia patients. Methods A retrospective cohort study was performed between pharmacist intervention and non-intervention groups. In this study, four types of failure were defined as the composite endpoint. When any one of the following failures occurred: 1) Death within 30 days from the start of VCM therapy, 2) Positive blood culture 7 days after the start of VCM therapy, 3) Change of VCM to another anti-MRSA agent, and 4) Development of nephrotoxicity, we considered that VCM treatment had failed. Survival time analysis was conducted with the Kaplan-Meier method and Cox’s proportional hazard model that included seven predefined parameters: pharmacist intervention, age, sex, weight, baseline VCM trough concentration, Charlson Comorbidity Index (CCI), and Pitt Bacteremia score (PBS). The effect of pharmacist intervention was studied as the survival probability estimated from the period of time from the start of VCM administration to the earliest failure. Results The survival rate at 30 days after starting VCM therapy, at the end of follow-up, was 53.1 and 82.1% in the non-intervention and intervention groups, respectively. A significant survival time prolongation was noted in the intervention group (p = 0.011, log rank test). Among the seven parameters, only pharmacist intervention was significantly different and its hazard ratio was 0.26 (p = 0.014). The survival probability of the intervention group was higher than that of the non-intervention group for the time to each failure. In subgroup analyses, a significant difference was noted in male patients between the intervention and non-intervention groups (p = 0.005). Age was categorized into those under and over 65 years old. For those over 65 years old, a significant difference was shown between the groups (p = 0.018). Conclusion To our knowledge, this is the first study to evaluate the failure of VCM treatment based on the composite endpoint. Pharmacist intervention through the initial VCM dose planning could maintain a balance between the efficacy and safety of VCM treatment and might avoid treatment failure for patients with MRSA bacteremia. Further investigations with large sample sizes are required to confirm our findings.
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  • 40
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    Publication Date: 2018-09-07
    Description: by Jiamin Wang, Shankun Zhao, Lianmin Luo, Yangzhou Liu, Zhiguo Zhu, Ermao Li, ZhiGang Zhao Objective To compare dorsal penile nerve block (DPNB) and eutectic mixture of local anesthetics (EMLA) cream for pain relief in infants during circumcision. Methods We systematically searched Medline via PubMed, Embase, CNKI and the Cochrane Library Center Register to identify randomized controlled trials up to March 2018. Effect estimates were performed in random effect models. Mean neonate infant pain scale (NIPS) scores, incidence of hematoma, edema and erythema, mean heart rate were conducted to assessed the effect of analgesia. We found that the EMLA had significantly higher pain scores compared to DPNB (SMD = 3.72, 95% CI 1.27–6.17, P = 0.003). In DPNB group, the incidence of hematoma was significantly higher than EMLA group, OR = 0.03, 95% CI 0.00–0.24, P = 0.001. The analysis did not show any significant differences in mean heart rate and the risk of edema and erythema between EMLA and DPNB group (SMD = 21.71, 95% CI = -0.88–44.30, P = 0.06 & OR = 0.40, 95% CI 0.15–1.07, P = 0.07 & OR = 7.33, 95% CI 0.84–64.07, P = 0.07). Conclusion Based on the pooled results from the included studies, we found that DPNB was significantly more effective in pain relief as indicated by mean NIPS score than EMLA in infants during circumcision. However, use of DPNB significantly increased the risk of hematoma.
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  • 41
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    Publication Date: 2018-09-07
    Description: by Amy Tasca, Kristina Astleford, Nicholas C. Blixt, Eric D. Jensen, Rajaram Gopalakrishnan, Kim C. Mansky Bone remodeling occurs via coupling between bone resorption by osteoclasts and bone formation by osteoblasts. The mechanisms that regulate osteoclast signals to osteoblasts are not well understood. Published studies have reported that BMP signaling in osteoclasts regulate osteoclast coupling targets. To investigate the necessity of canonical BMP signaling on osteoclast differentiation and coupling, we mated Smad1 fl/fl ; Smad5 fl/fl mice to c-Fms-Cre mice. We analyzed male mice at 3 months of age to determine the skeletal phenotype of the Smad1 fl/fl ; Smad5 fl/fl ;c-Fms-Cre (SMAD1/5 cKO) mice. There was a 1.2-fold decrease in trabecular BV/TV in SMAD1/5 cKO. Analyses of osteoclast serum markers in SMAD1/5 cKO mice, showed a significant increase in CTX-1 (1.5 fold) and TRAP ELISA (3 fold) compared to control mice. In these same mice, there was a 1.3-fold increase in cortical thickness. Consistent with the increase in cortical thickness, we found a 3-fold increase in osteoblast activity as measured by P1NIP ELISA assay from SMAD1/5 cKO mice. To explain the changes in cortical thickness and P1NP activity, we determined conditioned media from SMAD1/5 cKO osteoclast cultures enhanced mineralization of an osteoblast cell line and coupling factors expressed by osteoclasts that regulate osteoblast activity Wnt1 (4.5-fold increase), Gja1 (3-fold increase) and Sphk1 (1.5-fold increase) were all upregulated in osteoclasts from SMAD1/5 cKO compared to control osteoclasts. Lastly osteoclasts treated with dorsomorphin, a chemical inhibitor of SMAD1/5 signaling, demonstrates an increase in Wnt1 and Gja1 expression similar to the SMAD1/5 cKO mice. Previous studies demonstrated that TGF-β signaling in osteoclasts leads to increases in WNT1 expression by osteoclasts. Therefore, our data suggest that TGF-β and BMP signaling pathways in osteoclasts could act in an antagonistic fashion to regulate osteoblast activity through WNT1 and other coupling factors.
    Electronic ISSN: 1932-6203
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  • 42
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    Publication Date: 2018-09-07
    Description: by Chi-syuan Pan, Teressa Reanne Ju, Chi Chan Lee, Yu-Pei Chen, Chung-Y. Hsu, Dong-Zong Hung, Wei-Kung Chen, I-Kuan Wang Introduction Alcohol use disorder (AUD) is a spectrum of high risk behaviors including alcohol abuse and dependence. Chronic kidney disease (CKD) is progressive loss of renal function for more or equal to 3 months or presence of any irreversible kidney damage. Common risk factors of CKD have been identified, but the impact of alcohol consumption on kidney function is controversial. The study aims to investigate the relationship between alcohol use disorder and CKD on a national scale. Methods This retrospective cohort study was conducted using Taiwan’s National Health Insurance research database. Patients aged 20 years or older, without CKD and with the diagnosis of AUD (ICD-9-CM codes 303.X; 305.0, V113) from years 2000 to 2013 were enrolled. Control cohort was selected to match the demographics of the target population. Patients were followed until the end of 2013 or earlier if they developed CKD, died, or lost follow up. Baseline characteristics and comorbidities were identified for risk stratification. Results We identified 11639 patients in the AUD cohort and 46556 patients in the control cohort. Compared to patients in the control cohort, those in the AUD group were more likely to have multiple comorbidities (p 〈 0.001 for all comorbidities). After adjustment of age, gender, baseline comorbidities, and nonsteroidal anti-inflammatory drug use, the diagnosis of AUD was associated with an increased risk of CKD development (aHR = 1.62, 95% CI, 1.46–1.81).During the mean follow up periods of 6.47 (standard deviation (SD) = 3.80) years for the AUD cohort and 7.23 (SD = 3.75) years for the control cohort, the overall incidence density of CKD was significantly higher in patients with AUD than those in the control cohort (3.48 vs 6.51 per 1000 person-years, aHR = 1.68, 95% CI, 1.50–1.87). Kaplan-Meier analysis showed that the AUD cohort had a higher cumulative incidence of CKD than the control cohort (log-rank test, p value 〈 0.001). Patients with AUD had higher risks of CKD in all the stratified groups, except for the subgroup with age over 65 years old. Conclusion Our study suggested that AUD was associated with an increased incidence of newly diagnosed CKD by nearly two folds. Young age, in particular, had a higher association between AUD and CKD. Considering the preventable nature of AUD, establishing effective health policies is imperative to reduce high-risk alcohol behaviors and thereby prevent alcohol-related kidney disease. Further prospective studies are warranted to further elucidate the causation of AUD on kidney function.
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  • 43
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    Publication Date: 2018-09-07
    Description: by Eike A. Strathmann, Miriam Peters, Seyyedmohsen Hosseinibarkooie, Frank W. Rigo, C. Frank Bennett, Phillip G. Zaworski, Karen S. Chen, Michael Nothnagel, Brunhilde Wirth Objectives Spinal muscular atrophy (SMA) is a devastating motor neuron disorder caused by homozygous loss of the survival motor neuron 1 ( SMN1 ) gene and insufficient functional SMN protein produced by the SMN2 copy gene. Additional genetic protective modifiers such as Plastin 3 ( PLS3 ) can counteract SMA pathology despite insufficient SMN protein. Recently, Spinraza, an SMN antisense oligonucleotide (ASO) that restores full-length SMN2 transcripts, has been FDA- and EMA-approved for SMA therapy. Hence, the availability of biomarkers allowing a reliable monitoring of disease and therapy progression would be of great importance. Our objectives were (i) to analyse the feasibility of SMN and of six SMA biomarkers identified by the BforSMA study in the Taiwanese SMA mouse model, (ii) to analyse the effect of PLS3 overexpression on these biomarkers, and (iii) to assess the impact of low-dose SMN-ASO therapy on the level of SMN and the six biomarkers. Methods At P10 and P21, the level of SMN and six putative biomarkers were compared among SMA, heterozygous and wild type mice, with or without PLS3 overexpression, and with or without presymptomatic low-dose SMN-ASO subcutaneous injection. SMN levels were measured in whole blood by ECL immunoassay and of six SMA putative biomarkers, namely Cartilage Oligomeric Matrix Protein (COMP), Dipeptidyl Peptidase 4 (DPP4), Tetranectin (C-type Lectin Family 3 Member B, CLEC3B), Osteopontin (Secreted Phosphoprotein 1, SPP1), Vitronectin (VTN) and Fetuin A (Alpha 2-HS Glycoprotein, AHSG) in plasma. Results SMN levels were significantly discernible between SMA, heterozygous and wild type mice. However, no significant differences were measured upon low-dose SMN-ASO treatment compared to untreated animals. Of the six biomarkers, only COMP and DPP4 showed high and SPP1 moderate correlation with the SMA phenotype. PLS3 overexpression neither influenced the SMN level nor the six biomarkers, supporting the hypothesis that PLS3 acts as an independent protective modifier.
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  • 44
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    Publication Date: 2018-09-07
    Description: by Hui-Wen Lin, Li-Fong Lin, Hung-Chou Chen, Tsan-Hon Liou, Shih-Wei Huang Background Patients with chronic obstructive pulmonary disease (COPD) are at a higher risk of many types of cancer. However, specific investigation of the risk of prostate cancer and the influence of COPD pharmacotherapy in patients with COPD is lacking. This study investigated the risk and influence of COPD pharmacotherapy on risk of prostate cancer in patients with COPD. Methods This retrospective cohort study used data from Taiwan’s Longitudinal Health Insurance Database 2005 (LHID2005). The study cohort comprised COPD patients who received treatment between 2004 and 2008, and who were identified from the LHID2005. The control cohort comprised patients without COPD and was matched to the study cohort by age and sex. Two-stage propensity score calibration with the National Health Interview Survey 2005 was performed to obtain the missing confounders of smoking, alcohol drinking, and body mass index in the LHID. The hazard ratio (HR) and adjusted HR were estimated. Moreover, the influence of inhaled medications and other related medication on the risk of prostate cancer was analyzed by Cox proportional hazard regression. Results The COPD cohort comprised 12,774 patients, and the control cohort comprised 38,322 patients (1:3). The incidence of prostate cancer was 633 per 100,000 person-years in the COPD cohort and 361 per 100,000 person-years in the control cohort. The propensity score calibration-adjusted HR was 1.62 (95% CI, 1.40–1.87, p 〈 0.001) in the COPD cohort. Further analysis revealed that the adjusted HR for the risk of prostate cancer was 1.61 (95% CI, 1.19–2.16, p = 0.002) in patients with COPD who used short-acting muscarinic antagonists (SAMAs) and 1.89 (95% CI, 1.40–2.54, p 〈 0.001) in patients with COPD who used short-acting beta-agonists (SABAs). COPD patients had lower risk of prostate cancer when using statin (HR = 0.63, 95% CI, 0.45–0.89, p = 0.010) or aspirin (HR = 0.55, 95% CI, 0.35–0.85, p = 0.008). Conclusion Patients with COPD are at a higher risk of prostate cancer, particularly those using SAMAs or SABAs. This finding suggests that inflammation control may be an effective strategy for decreasing the risk of prostate cancer.
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  • 45
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    Publication Date: 2018-09-07
    Description: by Mi Soo Choi, Hee Seok Seo, Jong Gu Kim, Sung Jay Choe, Byung Cheol Park, Myung Hwa Kim, Seung Phil Hong Picosecond lasers have emerged as the leading technology for tattoo removal due to their shorter pulse lengths. To clarify the features of picosecond lasers, we compared picosecond and nanosecond lasers in their ability to remove multi-colored tattoo in an animal model. We first compared a nanosecond quality-switched Nd:YAG laser with picosecond Alexandrite and quality-switched Nd:YAG lasers and then the picosecond quality-switched Nd:YAG laser with the picosecond Alexandrite laser, using a guinea pig model. The colors in the tattoos included red, orange, yellow, green, blue, and black. Guinea pigs were treated for one session with each type of laser. The clearance of pigmentation and local reactions were evaluated based on clinical photographic assessment, quantitative assessment using a colorimeter, histopathology, and electron microscopic examination before laser treatment, immediately after, and at 3 weeks after the treatment. Regardless of pulse duration, a 532-nm laser was the most effective in clearing red, orange, and yellow pigments, although the overall effect and safety was better with the picosecond 532 nm laser. A picosecond 755 nm laser demonstrated excellent efficacy in removing only green and blue pigments. a picosecond 1064 nm laser demonstrated some effects on non-black colored tattoos. In terms of safety, picosecond lasers produced less tissue injury than nanosecond lasers. Conclusively, picosecond lasers are more effective and safer than nanosecond lasers.
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  • 46
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    Publication Date: 2018-09-07
    Description: by Yong Jae Lee, In Ha Lee, Yun-Ji Kim, Young Shin Chung, Jung-Yun Lee, Eun Ji Nam, Sunghoon Kim, Sang Wun Kim, Young Tae Kim Various kinetic parameters of serum CA-125 have been reported to have better correlation with outcomes for patients treated with neoadjuvant chemotherapy (NAC). This study aimed to compare the available kinetic parameters of serum CA-125 in an external cohort of advanced-stage ovarian cancer. Using the cancer registry databases from the Yonsei Cancer Hospital, we retrospectively reviewed 210 patients with advanced-stage ovarian cancer, treated with NAC followed by interval debulking surgery. We compared area under the receiver-operating characteristics curves (AUCs), false negative rate, and negative predictive value (NPV) using 10 different models for optimal cytoreduction and platinum resistance. In addition, we compared incremental AUC for progression-free survival (PFS) and overall survival (OS). No gross residual tumor was observed in 37.0% and residual tumors 0.6 for predicting optimal cytoreduction. After adjusting for age, BMI, disease stage, and histologic subtypes, all models had an AUC 〉0.70 for predicting platinum resistance. However, no model had a high enough NPV (highest value = 82.0%) to avoid chemotherapy futility. For survival outcomes, no model had an incremental AUC 〉0.70 for predicting either PFS or OS. None of the proposed serum CA-125 kinetic parameters showed high accuracy in predicting optimal cytoreduction, platinum resistance, or survival in patients receiving NAC. For advanced-stage ovarian cancer treated with NAC, there is a need to discover reliable biomarkers to better stratify patient response groups for optimal treatment decision-making.
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  • 47
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    Publication Date: 2018-09-07
    Description: by José Biurrun Manresa, Ole Kæseler Andersen, André Mouraux, Emanuel N. van den Broeke High frequency electrical stimulation (HFS) of the skin induces increased pinprick sensitivity in the surrounding unconditioned skin. The aim of the present study was to investigate the contribution of A-fiber nociceptors to this increased pinprick sensitivity. For this we assessed if the perception and brain responses elicited by low-intensity intra-epidermal electrical stimulation (IES), a method preferentially activating Aδ-fiber nociceptors, are increased in the area of HFS-induced increased pinprick sensitivity. HFS was delivered to one of the two forearms of seventeen healthy volunteers. Mechanical pinprick stimulation and IES were delivered at both arms before HFS (T0), 20 minutes after HFS (T1) and 45 minutes after HFS (T2). In all participants, HFS induced an increase in pinprick perception at the HFS-treated arm, adjacent to the site of HFS. This increase was significant at both T1 and T2. HFS did not affect the percept elicited by IES, but did enhance the magnitude of the N2 wave of IES-evoked brain potentials, both at T1 and at T2. Our results show that HFS induces a long-lasting enhancement of the N2 wave elicited by IES in the area of secondary hyperalgesia, indicating that HFS enhances the responsiveness of the central nervous system to nociceptive A-fiber input. However, we found no evidence that HFS affects the perception elicited by IES, which may suggest that the population of nociceptors that mediate the perception elicited by IES do not contribute to HFS-induced increased pinprick sensitivity.
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  • 48
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    Publication Date: 2018-09-07
    Description: by Christel Dagher, Tamara Salloum, Sahar Alousi, Harout Arabaghian, George F. Araj, Sima Tokajian The emergence of carbapenem resistant Escherichia coli represents a serious public health concern. This study investigated the resistome, virulence, plasmids content and clonality of 27 carbapenem resistant E . coli isolated from 27 hospitalized patients at the American University of Beirut Medical Center (AUBMC) in Lebanon between 2012 and 2016. Whole-genome sequencing (WGS) data were used to identify resistance determinants. Multilocus sequence typing (MLST), pulsed field gel electrophoresis (PFGE), phylogenetic grouping and PCR-based replicon typing (PBRT) were also performed. The 27 isolates were distributed into 15 STs, of which ST405 (14.8%; n = 4) was the most prevalent. All of the 27 isolates were carbapenem resistant and 20 (74%) were extended-spectrum β-lactamase (ESBL) gene carriers. The predominant detected carbapenemases were bla OXA-48 (48.1%; n = 13) and bla OXA-181 (7.4%; n = 2), for the ESBLs it was bla CTX-M-15 (55.6%; n = 15) and bla CTX-M-24 (18.5%; n = 5), and for the AmpC-type β–lactamases, bla CMY-42 (40.7%; n = 11) and bla CMY-2 (3.7%; n = 1). Thirteen replicons were identified among the 27 E . coli isolates including: IncL/M, IncFIA, IncFIB, IncFII, IncI1, and IncX3. PFGE revealed a high genetic diversity with the 27 isolates being grouped in 21 different pulsotypes. SNPs analysis and PFGE showed a possible clonal dissemination of ST405, ST1284, ST354 and ST410 and the dominance of certain STs, monitoring of which could help in elucidating routes of transmission. This study represents the first WGS-based in depth analysis of the resistomes and mobilomes of carbapenem resistant E . coli in Lebanon.
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  • 49
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    Publication Date: 2018-09-07
    Description: by Ewa Strauss, Jolanta Tomczak, Ryszard Staniszewski, Grzegorz Oszkinis Background Little is known on the role of selenoprotein genes in cardiovascular disease. This study examines the associations of the SEPP1 , SELENOS , TXNRD1 , TXNRD2 , GPX4 , and SOD2 polymorphisms and selenoprotein P (SeP) and thioredoxin concentrations with the development of abdominal aortic aneurysm (AAA) and aortoiliac occlusive disease (AOID), as well as their influence on cardiac phenotype. Methods 564 patients with AAA, 400 patients with AIOD, and 543 controls were enrolled and characterized for coronary artery disease, myocardial infarction, and systolic heart failure (HF) occurrence. In AAA, the coexistence of peripheral arterial disease (PAD) was examined. Genotypes were determined using TaqMan-based assays. Selenoprotein concentration was assessed using the ELISA method. Results The SELENOS rs34713741T , SEPP1 rs3877899A , and GPX4 rs713041T alleles were related to a 30–60% increase in the AIOD/PAD risk in the recessive or dominant model (all associations at P 〈 .05). The SEPP1 rs3877899A allele was a protective factor for the development of AAA without concomitant PAD (OR = 0.68 for the dominant model, P = .014), but not AAA with concomitant PAD. The cumulative two-locus effects of selenoprotein genes on the AAA/AIOD risk were observed, including the multiplicative interaction between the SELENOS rs34713741T and GPX4 rs713041T alleles (both in the recessive model) affecting the AIOD risk (OR = 5.27, P = .001) and its clinical phenotype. Coexistence of HF in aortic diseases was related to both the SEPP1 rs7579A allele (OR = 1.83 for carriers, P = .013) and increased SeP concentrations; SeP level ≥8.5 mg/mL caused a 3.5-fold increase in the risk of HF. In AAA, SeP levels were correlated with BMI ( r = -0.575, P 〈 .0001). Conclusions Our results provide evidence that selenoprotein polymorphisms constitute a risk factor for HF and peripheral atherosclerosis, but prevent the development of AAA. Excessive weight might result in reduced antioxidant reserve efficiency in AAA. Validation studies are required to establish whether SeP concentration may be a marker for HF.
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  • 50
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    Publication Date: 2018-09-07
    Description: by Eriko Hasumi, Katsuhito Fujiu, Toshiya Kojima, Osamu Kinoshita, Kan Nawata, Haruo Yamauchi, Minoru Ono, Issei Komuro Background Removal of cardiac implantable electronic devices (CIEDs) by manual traction during orthotopic heart transplantation (OHT) sometimes results in retained lead fragments. Moreover, abandoned leads and retained lead fragments are a contraindication for magnetic resonance imaging (MRI) and may be a cause of CIED infection. Objective To eliminate complications of retained lead fragments, we completely removed residual leads using an excimer laser sheath technique during OHT. We report our clinical experience and high success rate of lead extraction using the excimer laser sheath compared with manual traction during OHT. Methods and results We obtained data on 84 consecutive patients receiving OHT between August 2007 and August 2017. Thirty-nine of 84 patients had undergone CIED implantation before OHT and removal of all their leads was attempted during OHT. From 2007 to 2014, defibrillator and pacemaker leads were extracted by manual traction in all patients (N = 22). After 2015, all leads were extracted with the excimer laser sheath, and surgical assistance was prepared for the procedure (N = 17). Complete procedural success was achieved in 100% of patients in the excimer laser group and 77% of patients in the manual traction group. Conclusion Extraction of abandoned leads using the excimer laser sheath system during OHT is novel and safe technique, and has a higher success rate than extraction using manual traction during OHT.
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  • 51
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    Publication Date: 2018-09-07
    Description: by Cintia Lepesqueur, Scheila Scherrer, Marcos C. Vieira, Mário Almeida-Neto, Danielle M. Salcido, Lee A. Dyer, Ivone R. Diniz β diversity of herbivorous insects in the tropics is usually very high, and there is often strong dissimilarity in herbivore species composition across different spatial scales and different abiotic gradients. Similarly, turnover is high for trophic interactions between herbivorous insects and their host plants. Two factors have been proposed to explain temporal or spatial differences in trophic interactions: changes in species composition and temporal changes in the behavior of shared species. The goal of this study was to evaluate determinants of high β diversity of trophic interactions between lepidopteran caterpillars and their host plants across dry and rainy seasons and their transitions. Over the course of a year, interaction diversity data were collected from 275 temporary plots in Cerrado vegetation, comprising 257 species of caterpillars, 137 species of host plants and 503 different trophic interactions. All these diversity parameters varied across seasons. Species assemblages of caterpillars and plants were different among the four seasons, and there was a high turnover of interactions between the seasons. The high temporal β diversity of trophic interactions was mostly due to interaction rewiring between co-occurring species, as opposed to changes in species composition over time.
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  • 52
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    Publication Date: 2018-09-07
    Description: by Markus Künzler
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 53
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    Publication Date: 2018-09-07
    Description: by Meagan E. Sullender, Megan T. Baldridge
    Print ISSN: 1553-7366
    Electronic ISSN: 1553-7374
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  • 54
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    Publication Date: 2018-09-07
    Description: by John M. Halley, Kyle S. Van Houtan, Nate Mantua Human activities are exposing organisms not only to direct threats (e.g. habitat loss) but also to indirect environmental pressures such as climate change, which involves not just directional global warming but also increasing climatic variability. Such changes will impact whole communities of organisms and the possible effects on population dynamics have raised concerns about increased extinction rates. Conservation-minded approaches to extinction risk vary from range shifts predicted by climate envelope models with no population dynamics to population viability analyses that ignore environmental variability altogether. Our modelling study shows that these extremes are modelling responses to a spectrum of environmental sensitivity that organisms may exhibit. We show how the survival curve plays a major role in how environmental variability leads to population fluctuations. While it is often supposed that low-fecundity organisms (those with high parental investment) will be the most vulnerable to climate change, it is those with high fecundity (low parental investment) that are likely to be more sensitive to such changes. We also find that abundance variations in high fecundity populations is driven primarily by fluctuations in the survival of early life stages, the more so if those environmental changes are autocorrelated in time. We show which types of conservation actions are most appropriate for a number of real populations. While the most effective conservation actions for organisms of low fecundity is to avoid killing them, for populations with high fecundity (and low parental investment), our study suggests conservation should focus more on protecting early life stages from hostile environments.
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  • 55
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    Publication Date: 2018-09-07
    Description: by Nicolas Hegerle, Myeongjin Choi, James Sinclair, Mohammed N. Amin, Morgane Ollivault-Shiflett, Brittany Curtis, Rachel S. Laufer, Surekha Shridhar, Jerod Brammer, Franklin R. Toapanta, Ian Alan Holder, Marcela F. Pasetti, Andrew Lees, Sharon M. Tennant, Alan S. Cross, Raphael Simon Klebsiella pneumoniae (KP) and Pseudomonas aeruginosa (PA) are important human pathogens that are associated with a range of infection types, including wound and disseminated infections. Treatment has been complicated by rising rates of antimicrobial resistance. Immunoprophylactic strategies are not constrained by antimicrobial resistance mechanisms. Vaccines against these organisms would be important public health tools, yet they are not available. KP surface O polysaccharides (OPS) are protective antigens in animal models of infection. Similarly, PA flagellin (Fla), the major subunit of the flagellar filament, is required for virulence and is a target of protective antibodies in animal models. We report herein the development of a combined KP and PA glycoconjugate vaccine comprised of the four most common KP OPS types associated with human infections (O1, O2, O3, O5), chemically linked to the two Fla types of PA (FlaA, FlaB). Conjugation of KP OPS to PA Fla enhanced anti-polysaccharide immune responses and produced a formulation that generated antibody titers to the four KP OPS types and both PA Fla antigens in rabbits. Passive transfer of vaccine-induced rabbit antisera reduced the bacterial burden and protected mice against fatal intravenous KP infection. Mice passively transferred with conjugate-induced antisera were also protected against PA infection after thermal injury with a FlaB-expressing isolate, but not a FlaA isolate. Taken together, these promising preclinical results provide important proof-of-concept for a broad spectrum human vaccine to prevent KP and PA infections.
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-07
    Description: by Nnenna Nwogu, James R. Boyne, Samuel J. Dobson, Krzysztof Poterlowicz, G. Eric Blair, Andrew Macdonald, Jamel Mankouri, Adrian Whitehouse Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is recognised as the causative factor in the majority of MCC cases. The MCPyV small tumour antigen (ST) is considered to be the main viral transforming factor, however potential mechanisms linking ST expression to the highly metastatic nature of MCC are yet to be fully elucidated. Metastasis is a complex process, with several discrete steps required for the formation of secondary tumour sites. One essential trait that underpins the ability of cancer cells to metastasise is how they interact with adjoining tumour cells and the surrounding extracellular matrix. Here we demonstrate that MCPyV ST expression disrupts the integrity of cell-cell junctions, thereby enhancing cell dissociation and implicate the cellular sheddases, A disintegrin and metalloproteinase (ADAM) 10 and 17 proteins in this process. Inhibition of ADAM 10 and 17 activity reduced MCPyV ST-induced cell dissociation and motility, attributing their function as critical to the MCPyV-induced metastatic processes. Consistent with these data, we confirm that ADAM 10 and 17 are upregulated in MCPyV-positive primary MCC tumours. These novel findings implicate cellular sheddases as key host cell factors contributing to virus-mediated cellular transformation and metastasis. Notably, ADAM protein expression may be a novel biomarker of MCC prognosis and given the current interest in cellular sheddase inhibitors for cancer therapeutics, it highlights ADAM 10 and 17 activity as a novel opportunity for targeted interventions for disseminated MCC.
    Print ISSN: 1553-7366
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  • 57
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-08
    Description: by Ben J. Vincent, Max V. Staller, Francheska Lopez-Rivera, Meghan D. J. Bragdon, Edward C. G. Pym, Kelly M. Biette, Zeba Wunderlich, Timothy T. Harden, Javier Estrada, Angela H. DePace Hunchback is a bifunctional transcription factor that can activate and repress gene expression in Drosophila development. We investigated the regulatory DNA sequence features that control Hunchback function by perturbing enhancers for one of its target genes, even-skipped (eve) . While Hunchback directly represses the eve stripe 3+7 enhancer, we found that in the eve stripe 2+7 enhancer, Hunchback repression is prevented by nearby sequences—this phenomenon is called counter-repression. We also found evidence that Caudal binding sites are responsible for counter-repression, and that this interaction may be a conserved feature of eve stripe 2 enhancers. Our results alter the textbook view of eve stripe 2 regulation wherein Hb is described as a direct activator. Instead, to generate stripe 2, Hunchback repression must be counteracted. We discuss how counter-repression may influence eve stripe 2 regulation and evolution.
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  • 58
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    Publication Date: 2018-09-08
    Description: by Alexandre Blanckaert, Claudia Bank Hybridization has recently gained considerable interest both as a unique opportunity for observing speciation mechanisms and as a potential engine for speciation. The latter remains a controversial topic. It was recently hypothesized that the reciprocal sorting of genetic incompatibilities from parental species could result in hybrid speciation, when the hybrid population maintains a mixed combination of the parental incompatibilities that prevents further gene exchange with both parental populations. However, the specifics of the purging/sorting process of multiple incompatibilities have not been examined theoretically. We here investigate the allele-frequency dynamics of an isolated hybrid population that results from a single hybridization event. Using models of two or four loci, we investigate the fate of one or two genetic incompatibilities of the Dobzhansky-Muller type (DMIs). We study how various parameters affect both the sorting/purging of the DMIs and the probability of observing hybrid speciation by reciprocal sorting. We find that the probability of hybrid speciation is strongly dependent on the linkage architecture (i.e. the order and recombination rate between loci along chromosomes), the population size of the hybrid population, and the initial relative contributions of the parental populations to the hybrid population. We identify a Goldilocks zone for specific linkage architectures and intermediate recombination rates, in which hybrid speciation becomes highly probable. Whereas an equal contribution of parental populations to the hybrid population maximizes the hybrid speciation probability in the Goldilocks zone, other linkage architectures yield unintuitive asymmetric maxima. We provide an explanation for this pattern, and discuss our results both with respect to the best conditions for observing hybrid speciation in nature and their implications regarding patterns of introgression in hybrid zones.
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  • 59
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-08
    Description: by Ahmed Abdul Quadeer, David Morales-Jimenez, Matthew R. McKay Mutational correlation patterns found in population-level sequence data for the Human Immunodeficiency Virus (HIV) and the Hepatitis C Virus (HCV) have been demonstrated to be informative of viral fitness. Such patterns can be seen as footprints of the intrinsic functional constraints placed on viral evolution under diverse selective pressures. Here, considering multiple HIV and HCV proteins, we demonstrate that these mutational correlations encode a modular co-evolutionary structure that is tightly linked to the structural and functional properties of the respective proteins. Specifically, by introducing a robust statistical method based on sparse principal component analysis, we identify near-disjoint sets of collectively-correlated residues (sectors) having mostly a one-to-one association to largely distinct structural or functional domains. This suggests that the distinct phenotypic properties of HIV/HCV proteins often give rise to quasi-independent modes of evolution, with each mode involving a sparse and localized network of mutational interactions. Moreover, individual inferred sectors of HIV are shown to carry immunological significance, providing insight for guiding targeted vaccine strategies.
    Print ISSN: 1553-734X
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  • 60
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-08
    Description: by Kittipong Maneechotesuwan, Xin Yao, Kazuhiro Ito, Elen Jazrawi, Omar S. Usmani, Ian M. Adcock, Peter J. Barnes
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
    Topics: Medicine
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  • 61
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-08
    Description: by Valeriya Gritsenko, Russell L. Hardesty, Matthew T. Boots, Sergiy Yakovenko
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 62
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-08
    Description: by The PLOS ONE Staff
    Electronic ISSN: 1932-6203
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  • 63
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    Publication Date: 2018-09-08
    Description: by Jessica S. Gubbels, Kelly Stessen, Ilona van de Kolk, Nanne K. de Vries, Carel Thijs, Stef P. J. Kremers Background Our knowledge of the role of parental and child-care staff behavior in the development and prevention of obesity is rapidly increasing. Potential interaction between both settings in so-called meso-systems, as hypothesized by the ecological systems perspective, is however often ignored. Specifically, inconsistency between home and child-care is hypothesized to have negative effects on child outcomes. Methods Participants were recruited through 23 child-care centers in the Netherlands. Data regarding 161 child-parent-child-care staff triads were available. Parenting and child care practices were assessed using validated questionnaires for parents (Child Feeding Practices Questionnaire, Preschooler Physical Activity Parenting Practices instrument) and child-care staff (Child-care Food and Activity Practices Questionnaire), using similar items in both settings. Absolute difference scores between parents and child-care staff were calculated for each triad as a measure of meso-system consistency. Child outcomes were physical activity (as assessed by accelerometry), dietary intake (from the parental questionnaire), and measured BMI z-scores. Paired t-tests were used to examine consistency between practices in both settings. Linear regression analyses were used to explore the association of parenting practices, child-care practices and difference scores on the one hand, and child outcomes on the other. Results Significant differences between settings were found for almost all practices, and in most cases child-care staff scores more favorable on the practices than parents. Inconsistencies were mostly associated with unhealthy dietary intake and lower physical activity levels, but not with BMI. Conclusion The current study showed that inconsistencies in parenting and child-care practices exist, and that these inconsistencies seem to be associated with unhealthy behavior in children. The results underline the importance of studying meso-system influences on behavior in general, and children’s energy balance-related behavior specifically.
    Electronic ISSN: 1932-6203
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  • 64
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by Haojun Yang, Martina Ralle, Michael J. Wolfgang, Neha Dhawan, Jason L. Burkhead, Susana Rodriguez, Jack H. Kaplan, G. William Wong, Norman Haughey, Svetlana Lutsenko Copper (Cu) has emerged as an important modifier of body lipid metabolism. However, how Cu contributes to the physiology of fat cells remains largely unknown. We found that adipocytes require Cu to establish a balance between main metabolic fuels. Differentiating adipocytes increase their Cu uptake along with the ATP7A-dependent transport of Cu into the secretory pathway to activate a highly up-regulated amino-oxidase copper-containing 3 (AOC3)/semicarbazide-sensitive amine oxidase (SSAO); in vivo, the activity of SSAO depends on the organism’s Cu status. Activated SSAO oppositely regulates uptake of glucose and long-chain fatty acids and remodels the cellular proteome to coordinate changes in fuel availability and related downstream processes, such as glycolysis, de novo lipogenesis, and sphingomyelin/ceramide synthesis. The loss of SSAO-dependent regulation due to Cu deficiency, limited Cu transport to the secretory pathway, or SSAO inactivation shifts metabolism towards lipid-dependent pathways and results in adipocyte hypertrophy and fat accumulation. The results establish a role for Cu homeostasis in adipocyte metabolism and identify SSAO as a regulator of energy utilization processes in adipocytes.
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    Electronic ISSN: 1545-7885
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  • 65
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by Fridolin Gross, Paolo Bonaiuti, Silke Hauf, Andrea Ciliberto The mitotic checkpoint (also called spindle assembly checkpoint) is a signaling pathway that ensures faithful chromosome segregation. Mitotic checkpoint proteins inhibit the anaphase-promoting complex (APC/C) and its activator Cdc20 to prevent precocious anaphase. Checkpoint signaling leads to a complex of APC/C, Cdc20, and checkpoint proteins, in which the APC/C is inactive. In principle, this final product of the mitotic checkpoint can be obtained via different pathways, whose relevance still needs to be fully ascertained experimentally. Here, we use mathematical models to compare the implications on checkpoint response of the possible pathways leading to APC/C inhibition. We identify a previously unrecognized funneling effect for Cdc20, which favors Cdc20 incorporation into the inhibitory complex and therefore promotes checkpoint activity. Furthermore, we find that the presence or absence of one specific assembly reaction determines whether the checkpoint remains functional at elevated levels of Cdc20, which can occur in cancer cells. Our results reveal the inhibitory logics behind checkpoint activity, predict checkpoint efficiency in perturbed situations, and could inform molecular strategies to treat malignancies that exhibit Cdc20 overexpression.
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    Publication Date: 2018-09-11
    Description: by Tatu Pantsar, Sami Rissanen, Daniel Dauch, Tuomo Laitinen, Ilpo Vattulainen, Antti Poso A mutated KRAS protein is frequently observed in human cancers. Traditionally, the oncogenic properties of KRAS missense mutants at position 12 (G12X) have been considered as equal. Here, by assessing the probabilities of occurrence of all KRAS G12X mutations and KRAS dynamics we show that this assumption does not hold true. Instead, our findings revealed an outstanding mutational bias. We conducted a thorough mutational analysis of KRAS G12X mutations and assessed to what extent the observed mutation frequencies follow a random distribution. Unique tissue-specific frequencies are displayed with specific mutations, especially with G12R, which cannot be explained by random probabilities. To clarify the underlying causes for the nonrandom probabilities, we conducted extensive atomistic molecular dynamics simulations (170 μs) to study the differences of G12X mutations on a molecular level. The simulations revealed an allosteric hydrophobic signaling network in KRAS, and that protein dynamics is altered among the G12X mutants and as such differs from the wild-type and is mutation-specific. The shift in long-timescale conformational dynamics was confirmed with Markov state modeling. A G12X mutation was found to modify KRAS dynamics in an allosteric way, which is especially manifested in the switch regions that are responsible for the effector protein binding. The findings provide a basis to understand better the oncogenic properties of KRAS G12X mutants and the consequences of the observed nonrandom frequencies of specific G12X mutations.
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    Publication Date: 2018-09-11
    Description: by Haroon Ahmed, Daniel Farewell, Nick A. Francis, Shantini Paranjothy, Christopher C. Butler Background Few studies have investigated the risk of adverse outcomes in older people with renal impairment presenting to primary care with a urinary tract infection (UTI). The aim of this study was to determine the risk of adverse outcomes in patients aged ≥65 years presenting to primary care with a UTI, by estimated glomerular filtration rate (eGFR) and empirical prescription of nitrofurantoin versus trimethoprim. Methods and findings This was a retrospective cohort study using linked health record data from 795,484 patients from 393 general practices in England, who were aged ≥65 years between 2010 and 2016. Patients were entered into the cohort if they presented with a UTI and had a creatinine measurement in the 24 months prior to presentation. We calculated an eGFR to estimate risk of adverse outcomes by renal function, and propensity-score matched patients with eGFRs 60 mL/minute/1.73 m 2 , patients with an eGFR of
    Print ISSN: 1549-1277
    Electronic ISSN: 1549-1676
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  • 68
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    Publication Date: 2018-09-11
    Description: by Arianne C. Richard, James E. Peters, Natalia Savinykh, James C. Lee, Eric T. Hawley, Françoise Meylan, Richard M. Siegel, Paul A. Lyons, Kenneth G. C. Smith Chronic inflammation in inflammatory bowel disease (IBD) results from a breakdown of intestinal immune homeostasis and compromise of the intestinal barrier. Genome-wide association studies have identified over 200 genetic loci associated with risk for IBD, but the functional mechanisms of most of these genetic variants remain unknown. Polymorphisms at the TNFSF15 locus, which encodes the TNF superfamily cytokine commonly known as TL1A, are associated with susceptibility to IBD in multiple ethnic groups. In a wide variety of murine models of inflammation including models of IBD, TNFSF15 promotes immunopathology by signaling through its receptor DR3. Such evidence has led to the hypothesis that expression of this lymphocyte costimulatory cytokine increases risk for IBD. In contrast, here we show that the IBD-risk haplotype at TNFSF15 is associated with decreased expression of the gene by peripheral blood monocytes in both healthy volunteers and IBD patients. This association persists under various stimulation conditions at both the RNA and protein levels and is maintained after macrophage differentiation. Utilizing a “recall-by-genotype” bioresource for allele-specific expression measurements in a functional fine-mapping assay, we localize the polymorphism controlling TNFSF15 expression to the regulatory region upstream of the gene. Through a T cell costimulation assay, we demonstrate that genetically regulated TNFSF15 has functional relevance. These findings indicate that genetically enhanced expression of TNFSF15 in specific cell types may confer protection against the development of IBD.
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  • 69
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    Publication Date: 2018-09-11
    Description: by Stéphanie Gay, Jérôme Bugeon, Amine Bouchareb, Laure Henry, Clara Delahaye, Fabrice Legeai, Jérôme Montfort, Aurélie Le Cam, Anne Siegel, Julien Bobe, Violette Thermes Female gamete production relies on coordinated molecular and cellular processes that occur in the ovary throughout oogenesis. In fish, as in other vertebrates, these processes have been extensively studied both in terms of endocrine/paracrine regulation and protein expression and activity. The role of small non-coding RNAs in the regulation of animal reproduction remains however largely unknown and poorly investigated, despite a growing interest for the importance of miRNAs in a wide variety of biological processes. Here, we analyzed the role of miR-202, a miRNA predominantly expressed in male and female gonads in several vertebrate species. We studied its expression in the medaka ovary and generated a mutant line (using CRISPR/Cas9 genome editing) to determine its importance for reproductive success with special interest for egg production. Our results show that miR-202-5p is the most abundant mature form of the miRNA and that it is expressed in granulosa cells and in the unfertilized egg. The knock out (KO) of mir-202 gene resulted in a strong phenotype both in terms of number and quality of eggs produced. Mutant females exhibited either no egg production or produced a dramatically reduced number of eggs that could not be fertilized, ultimately leading to no reproductive success. We quantified the size distribution of the oocytes in the ovary of KO females and performed a large-scale transcriptomic analysis approach to identified dysregulated molecular pathways. Together, cellular and molecular analyses indicate that the lack of miR-202 impairs the early steps of oogenesis/folliculogenesis and decreases the number of large ( i . e . vitellogenic) follicles, ultimately leading to dramatically reduced female fecundity. This study sheds new light on the regulatory mechanisms that control the early steps of follicular development, including possible targets of miR-202-5p, and provides the first in vivo functional evidence that a gonad-predominant microRNA may have a major role in female reproduction.
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  • 70
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    Publication Date: 2018-09-11
    Description: by Nicole Marquardt, Malte Feja, Hana Hünigen, Johanna Plendl, Lena Menken, Heidrun Fink, Bettina Bert In the European Union (EU) millions of laboratory mice are used and killed for experimental and other scientific purposes each year. Although controversially discussed, the use of carbon dioxide (CO 2 ) is still permitted for killing rodents according to the Directive 2010/63/EU. Within the scope of refinement, our aim was to investigate if isoflurane and sevoflurane are an appropriate alternative killing method to CO 2 in mice. Different concentrations of CO 2 (filling rates of 20%, 60%, 100%; CO 2 20, 60, 100), isoflurane (Iso 2%, 5%) and sevoflurane (Sevo 4.8%, 8%) were compared in two mouse strains (NMRI, C57Bl/6J) using a broad spectrum of behavioral parameters, including the approach-avoidance test, and analyzing blood for stress parameters (glucose, adrenaline, noradrenaline). We focused in our study on the period from the beginning of the gas inlet to loss of consciousness, as during this period animals are able to perceive pain and distress. Our results show that only higher concentrations of CO 2 (CO 2 60, 100) and isoflurane (5%) induced surgical tolerance within 300 s in both strains, with CO 2 100 being the fastest acting inhalant anesthetic. The potency of halogenated ethers depended on the mouse strain, with C57Bl/6J being more susceptible than NMRI mice. Behavioral analysis revealed no specific signs of distress, e. g. stress-induced grooming, and pain, i. e. audible vocalizations, for all inhalant gases. However, adrenaline and noradrenaline plasma concentrations were increased, especially in NMRI mice exposed to CO 2 in high concentrations, whereas we did not observe such increase in animals exposed to isoflurane or sevoflurane. Escape latencies in the approach-avoidance test using C57Bl/6J mice did not differ between the three inhalant gases, however, some animals became recumbent during isoflurane and sevoflurane but not during CO 2 exposure. The rise in catecholamine concentrations suggests that CO 2 exposure might be linked to a higher stress response compared to isoflurane and sevoflurane exposure, although we did not observe a behavioral correlate for that. Follow-up studies investigating other fast-acting stress hormones and central anxiety circuits are needed to confirm our findings.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-09-11
    Description: by Matthias Zielonka, Maximilian Breuer, Jürgen Günther Okun, Matthias Carl, Georg Friedrich Hoffmann, Stefan Kölker Hyperammonemia is the common biochemical hallmark of urea cycle disorders, activating neurotoxic pathways. If untreated, affected individuals have a high risk of irreversible brain damage and mortality. Here we show that acute hyperammonemia strongly enhances transamination-dependent formation of osmolytic glutamine and excitatory glutamate, thereby inducing neurotoxicity and death in ammoniotelic zebrafish larvae via synergistically acting overactivation of NMDA receptors and bioenergetic impairment induced by depletion of 2-oxoglutarate. Intriguingly, specific and irreversible inhibition of ornithine aminotransferase (OAT) by 5-fluoromethylornithine rescues zebrafish from lethal concentrations of ammonium acetate and corrects hyperammonemia-induced biochemical alterations. Thus, OAT inhibition is a promising and effective therapeutic approach for preventing neurotoxicity and mortality in acute hyperammonemia.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-09-11
    Description: by Yoelis Yepes-Pérez, Carolina López, Carlos Fernando Suárez, Manuel Alfonso Patarroyo Malaria is an infectious disease caused by parasites from the genus Plasmodium (P . falciparum and P . vivax are responsible for 90% of all clinical cases); it is widely distributed throughout the world’s tropical and subtropical regions. The P . vivax Pv 12 protein is involved in invasion, is expressed on merozoite surface and has been recognised by antibodies from individuals exposed to the disease. In this study, B- and T-cell epitopes from Pv 12 were predicted and characterised to advance in the design of a peptide-based vaccine against malaria. For evaluating the humoral response of individuals exposed to natural P . vivax infection from two endemic areas in Colombia, BepiPred-1.0 software was used for selecting B-cell epitopes. B-cell epitope 39038 displayed the greatest recognition by naturally-acquired antibodies and induced an IgG2/IgG4 response. NetMHCIIpan-3.1 prediction software was used for selecting peptides having high affinity binding for HLA-DRβ1* allele lineages and this was confirmed by in-vitro binding assays. T-epitopes 39113 and 39117 triggered a memory T-cell response (Stimulation Index≥2) and significant cytokine production. Combining in-silico , in-vitro and functional assays, two Pv 12 protein regions (containing peptides 39038, 39040, 39113 and 39117) have thus been characterised as promising vaccine candidates against P . vivax malaria.
    Electronic ISSN: 1932-6203
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    Publication Date: 2018-09-11
    Description: by Sunyoung Park, Myung-Sun Kim This study used event-related potentials (ERPs) and a modified spatial 2 -back task to investigate spatial working memory in binge drinking (BD) college students. Based on the Korean version of the Alcohol Use Disorder Identification Test (AUDIT-K) and Alcohol Use Questionnaire (AUQ) scores, participants were assigned into BD ( n = 25) and non-BD ( n = 25) groups. The modified spatial 2 -back task includes congruent, incongruent, and lure conditions and participants are required to respond as rapidly and accurately as possible to the congruent stimuli but not to the incongruent and lure stimuli. The BD and non-BD groups exhibited comparable performances on the spatial 2 -back task but the BD group showed significantly larger P3 amplitudes than the non-BD group. Additionally, the non-BD group showed larger P3 amplitudes in response to the congruent stimuli compared to the incongruent and lure stimuli whereas the P3 amplitudes in the BD group did not differ significantly among the three conditions. These results indicate that the BD individuals exerted greater effort to maintain performance levels comparable to non-BD individuals and that they were less efficient in differentiating or allocating attentional resources between relevant and irrelevant information.
    Electronic ISSN: 1932-6203
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  • 74
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    Publication Date: 2018-09-11
    Description: by Xiao Han, Baoli Yin, Shengli Lin, Qian Wang, Ni Su, Cuilian Zhang Objective To investigate factors that influence maternal hCG concentration in early pregnancy and the relationship between hCG concentration in early pregnancy and basal FSH (bFSH) level. Design Retrospective cohort study. Setting Reproductive medical center. Patient(s) In total, 482 women aged 22 to 38 years with elevated basal FSH (〉 10 IU/L) and who experienced a single live birth after in vitro fertilization-embryo transfer were selected. These 482 women were age-matched with an equal number of women with normal basal FSH (≤10 IU/L) who also experienced a single live birth. Intervention(s) None. Main Outcome Measure(s) HCG concentration. Result(s) The hCG concentrations on Day 14 and Day 21 were 560.46 (363.63–842.52) IU/L and 9862.00 (6512.25–14029.50) IU/L, respectively, in the elevated bFSH group, and these values were significantly increased compared with the normal bFSH group. After adjusting for confounding factors, the concentrations of maternal hCG on Day 14 and Day 21 were significantly associated with basal FSH. In addition, crude linear regression analysis demonstrated that hCG concentrations increased as the basal serum levels of FSH increased. Conclusion(s) Elevated basal FSH has implications for the interpretation of hCG concentrations in early pregnancy after in vitro fertilization-embryo transfer (IVF-ET) that led to a single live birth.
    Electronic ISSN: 1932-6203
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  • 75
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    Publication Date: 2018-09-11
    Description: by Rafael Campos, Alberto Fernando Oliveira Justo, Fabíola Z. Mónica, José Carlos Cogo, Ronilson Agnaldo Moreno, Valéria Barbosa de Souza, Andre Almeida Schenka, Gilberto De Nucci Endothelium is the main source of catecholamine release in the electrical-field stimulation (EFS)–induced aortic contractions of the non- venomous snake Panterophis guttatus . However, adrenergic vasomotor control in venomous snakes such as Crotalus durissus terrificus and Bothrops jararaca has not yet been investigated. Crotalus and Bothrops aortic rings were mounted in an organ bath system. EFS-induced aortae contractions were performed in the presence and absence of guanethidine (30 μM), phentolamine (10 μM) or tetrodotoxin (1 μM). Frequency-induced contractions were also performed in aortae with endothelium removed. Immunohistochemical localization of both tyrosine hydroxylase (TH) and S-100 protein in snake aortic rings and brains, as well as in human tissue (paraganglioma tumour) were carried out. EFS (4 to 16 Hz) induced frequency-dependent aortic contractions in both Crotalus and Bothrops . The EFS-induced contractions were significantly reduced in the presence of either guanethidine or phentolamine in both snakes (p
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  • 76
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    Publication Date: 2018-09-11
    Description: by J’Neka S. Claxton, Richard F. MacLehose, Pamela L. Lutsey, Faye L. Norby, Lin Y. Chen, Wesley T. O’Neal, Alanna M. Chamberlain, Lindsay G. S. Bengtson, Alvaro Alonso Background No scores presently exist to predict bleeding in atrial fibrillation (AF) populations using direct oral anticoagulants (DOACs). We used data from two independent healthcare claims databases to develop and validate a predictive model of major bleeding in a contemporary AF population. Methods Patients with non-valvular AF initiating oral anticoagulation were identified in the MarketScan databases from 2007–2014. Using Cox regression models in 1000 bootstrapped samples, we developed a model that selected variables predicting major bleeding in the first year after anticoagulant initiation. The final model was validated in patients with non-valvular AF in the Optum Clinformatics database in the period 2009–2015. The discriminative ability of existing bleeding scores were individually evaluated and compared with the new bleeding model termed Anticoagulation-specific Bleeding Score (ABS) in both MarketScan and Optum. Results Among 119,083 patients with AF initiating oral anticoagulation in the derivation cohort, 4,030 experienced a bleeding event. The variable selection model identified 15 variables (including individual type of oral anticoagulant) associated with major bleeding. Discrimination of the model was modest [c-statistic 0.68, 95% confidence interval (CI) 0.67–0.69]. The model was subsequently applied to 81,285 AF patients in the validation data set (3,238 bleeding events), showing similar discrimination (c-statistic 0.68, 95% CI 0.67–0.69). In both cohorts, the predictive performance of the ABS was better than the existing models for bleeding prediction in AF. Conclusions We developed a model that uses administrative healthcare data for the identification of AF patients at higher risk of bleeding after initiation of oral anticoagulation, taking into account the lower bleeding risk in DOAC compared to warfarin users.
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by Sumit Kumar Das, Laishram Ladusingh Introduction There is an evidence of increasing inpatient expenditure for decedents. Estimates used to assess the economic burden of out-of-pocket (OOP) healthcare expenditure provide an underestimation for inpatient decedent cases. The aims of this paper are to study the trend and pattern of inpatient decedent expenditure and decipher the reasons behind the increasing cost in India. Methods Using three rounds of national level National Sample Survey (NSS) data on morbidity & healthcare conducted during 1995–2015 in India, total and component-wise cost of dying was estimated by the socio-demographic characteristics and types of diseases. Generalised linear model was employed to find the changing effect of inpatient decedents on inpatient expenditure on three-time points. Results More than half among inpatient decedents were elderly. Mean inpatient expenditure for neoplasm, circulatory system-related diseases and external causes of mortality and morbidity increased substantially during these two decades. Mean decedent inpatient expenditure become double, diagnostic and bed charges increased by 243%, 323% respectively during 2004–05 to 2014–15. During 2014–15 average decedents aged 15–59 years spent ₹53599 in last twelve month of their life. Controlling all other potential factors, the inpatient expenditure among decedents increased substantially between 1995–96 and 2014–15. Discussion Out-of-pocket inpatient health expenditure widened between survivor and decedents in between 1995–2014. Increase in the proportion of elderly, proportion of non-communicable and lifestyle-related diseases, expenses on drugs, diagnostics, bed charges largely private sector expenses were the leading reasons for increasing inpatient decedent expenditure. Age-based risk adjustment and modification of end-of-life care are strongly required, future social insurance based on the health-based value of out-of-pocket expenditure rather than their pure consumption value need to be designed to tackle the burden.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 78
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by Trenton Agrelius, Jeffry L. Dudycha, James T. Morris Spartina alterniflora , marsh grass, is a vegetative apomicticly-reproducing halophyte native to marshes along the east coast of the United States and invasive across the world. S . alterniflora provides many ecosystem services including, but not limited to, water filtration, habitats for invertebrates, and sediment retention. Widespread diebacks of longstanding marsh grass colonies launched extensive investigations into probable mechanisms leading to patchy diebacks. There is still current debate as to the causes of a marsh dieback but environmental stress is acknowledged as a constant. Spatial epigenetic variation could contribute to variation of stress susceptibility, but the scale and structure of epigenetic variation is unknown. The current study investigates patterns of epigenetic variation in a natural population of S . alterniflora . This study examines variation of global DNA methylation within and among clones of the marsh grass Spartina alterniflora using an ELISA-like microplate reaction and observed significant heterogeneity of global DNA methylation within and among clones of S . alterniflora across the North Inlet basin, as well as significant differences of global methylation between adults and sexually produced seedlings. The present study also characterized differences for plants in a section of the population that experienced an acute marsh dieback in the year 2001 and have subsequently recolonized, finding a significant positive correlation between cytosine methylation and time period of colonization. The significant heterogeneity of global DNA methylation both within and among clones observed within this natural population of S . alterniflora and potential impacts from hypersaline environments at North Inlet suggests the need for more in-depth epigenetic studies to fully understand DNA methylation within an ecological context. Future studies should consider the effects of varying saline conditions on both global DNA and gene specific methylation.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 79
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by Yun Wang, Li Wen, Shi Zhou, Yong Zhang, Xin-Hao Wang, You-Yu He, Allan Davie, Suzanne Broadbent Aims The aims of this study were to determine the effects of four weeks of intermittent exposure to a moderate hypoxia environment (15% oxygen), and compare with the effects of exercise in normoxia or hypoxia, on glucose homeostasis, insulin sensitivity, GLUT4 translocation, insulin receptor phosphorylation, Akt-dependent GSK3 phosphorylation and Akt activity in skeletal muscle of obese mice with type 2 diabetes. Methods C57BL/6J mice that developed type 2 diabetes with a high-fat-diet (55% fat) (fasting blood glucose, FBG = 13.9 ± 0.69 (SD) mmol/L) were randomly allocated into diabetic control (DC), rest in hypoxia (DH), exercise in normoxia (DE), and exercise in hypoxia (DHE) groups (n = 7, each), together with a normal-diet (4% fat) control group (NC, FBG = 9.1 ± 1.11 (SD) mmol/L). The exercise groups ran on a treadmill at intensities of 75–90% VO 2 max. The interventions were applied one hour per day, six days per week for four weeks. Venous blood samples were analysed for FBG, insulin (FBI) and insulin sensitivity (QUICKI) pre and post the intervention period. The quadriceps muscle samples were collected 72 hours post the last intervention session for analysis of GLUT4 translocation, insulin receptor phosphorylation, Akt expression and phosphorylated GSK3 fusion protein by western blot. Akt activity was determined by the ratio of the phosphorylated GSK3 fusion protein to the total Akt protein. Results The FBG of the DH, DE and DHE groups returned to normal level (FBG = 9.4 ± 1.50, 8.86 ± 0.94 and 9.0 ± 1.13 (SD) mmol/L for DH, DE and DHE respectively, P 〈 0.05), with improved insulin sensitivity compared to DC (P 〈 0.05), after the four weeks treatment, while the NC and DC showed no significant changes, as analysed by general linear model with repeated measures. All three interventions resulted in a significant increase of GLUT4 translocation to cell membrane compared to the DC group (P 〈 0.05). The DE and DH showed a similar level of insulin receptor phosphorylation compared with NC that was significantly lower than the DC (P 〈 0.05) post intervention. The DH and DHE groups showed a significantly higher Akt activity compared to the DE, DC and NC (P 〈 0.05) post intervention, as analysed by one-way ANOVA. Conclusions This study produced new evidence that intermittent exposure to mild hypoxia (0.15 FiO 2 ) for four weeks resulted in normalisation of FBG, improvement in whole body insulin sensitivity, and a significant increase of GLUT4 translocation in the skeletal muscle, that were similar to the effects of exercise intervention during the same time period, in mice with diet-induced type 2 diabetes. However, exercise in hypoxia for four weeks did not have additive effects on these responses. The outcomes of the research may contribute to the development of effective, alternative and complementary interventions for management of hyperglycaemia and type 2 diabetes, particularly for individuals with limitations in participation of physical activity.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 80
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by Minu Bharati, Dhiraj Saha Background Mosquitoes belonging to genus Aedes are the prime vectors of several arboviral diseases such as Dengue, Zika and Chikungunya worldwide. Every year numerous cases of dengue infections occur throughout the world, proper control of which depends on efficient vector control. However the onset of insecticide resistance has resulted in failure of vector control approaches. Principal findings This study was carried out to unveil the degree of prevailing insecticide resistance along with its underlying mechanisms among the primary dengue vector in dengue endemic districts of West Bengal, India through standard WHO protocol. It was observed that, the majority of the tested populations were found to possess resistance to more than one insecticide. In adult bioassay, the toxicity levels of the six tested insecticides was found to decrease in the following order: deltamethrin 〉 lambdacyhalothrin 〉 malathion 〉 propoxur 〉 permethrin 〉 DDT. In larval bioassay, one of the tested populations was found to possess moderate resistance against temephos, mortality percentage 92.5% and 79.8% for WHO (0.0200 ppm) and National Vector Borne disease Programme, India recommended dose (0.0125 ppm) respectively. Carboxylesterases were found to be involved in conferring resistance as revealed in synergistic and quantitative assay against temephos in North Dinajpur (NDP) population and malathion in Alipurduar (APD) and Darjeeling (DAR) populations. Similar correlations were also observed in the majority of the tested populations between reduced susceptibilities against pyrethroid insecticides and Cytochrome P 450 s activity. Conclusion Efficient disease management in this region can only be achieved through proper integrated vector management along with tools to minimize insecticide resistance. This study may help the concerned authorities in the formulation of an effective vector control strategy throughout this region incorporating the knowledge gained through this study.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 81
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by David López-Idiáquez, Pablo Vergara, Juan Antonio Fargallo, Jesús Martínez-Padilla The cost of reproduction is a key concept in life-history trade-offs. However, our understanding of the reproductive costs is biased towards measures of reproductive effort obtained before offspring independence. During the post-fledging dependence period (PFDP), it is well known that parents feed and protect their offspring. However, the effort devoted to this reproductive activity has never been considered in the context of of the costs of reproduction. Moreover, the potential fitness benefits and costs for offspring and parents, respectively, of the duration of the PFDP are largely unknown. We estimated the duration of the PFDP over 5 years using wild common kestrels ( Falco tinnunculus ) and studied its association with survival probability and future parental reproductive performance. Our results show that longer PFDPs increase the survival probability of fledglings, probably due to the benefits obtained from parental care. In addition, we found that providing longer PFDPs was associated with reduced clutch sizes but not the number of fledglings in the subsequent breeding season in males. We suggest that increased parental expenditures on offspring during the PFDP may represent a potential cost of reproduction in breeding males.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 82
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by Siyu Xu, Jihua Zhu, Zutao Jiang, Zhiyang Lin, Jian Lu, Zhongyu Li This paper proposes a global approach for the multi-view registration of unordered range scans. Our method starts with the pair-wise registration, where multi-scale descriptor is selected for feature point and the propagation of feature correspondence is accordingly accelerated. Subsequently, we design an effective rule to judge the reliability of these pair-wise registration results. According to the judgment of reliability, we propose a model fusion method, which can utilize reliable results of pair-wise registration to augment the model shape. Finally, multi-view registration can be achieved by operating the pair-wise registration, reliability judgment, and model fusion alternately. The proposed approach can be applied to scene reconstruction and robot mapping. Experimental results conducted on public datasets show that the proposed approach can automatically achieve multi-view registration of unordered range scans. Compared with other related approaches, the proposed approach has superior performances in accuracy and effectiveness.
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
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  • 83
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by Chi-Wei Su, Xiao-Cui Yin, Ran Tao In this paper, we revisit the relationship between housing prices and consumption in China by using a continuous wavelet analysis. This method provides an insight into the dynamic nexus in both time and frequency domains. In general, Empirical results show that there is a positive relationship between the two series in China, although it varies across time and frequencies. First, we find that disposable income is the core factor which affects both consumption and housing prices in China. Second, housing prices have a weak wealth effect on consumption in most time. High housing ownership and proportion of housing asset in the total household asset lead to a wealth effect of housing prices on consumption. Third, in the long term, there is a significant wealth effect of housing prices on consumption, but it weakens after 2008, which implies that excessively high housing prices in recent years have partially constrained residents’ consumption. These findings have important implications for seeking housing market regulation and expanding domestic consumption decisions.
    Electronic ISSN: 1932-6203
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  • 84
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    Public Library of Science (PLoS)
    Publication Date: 2018-09-11
    Description: by Rosana Gonzalez-Quintial, Anthony Nguyen, Dwight H. Kono, Michael B. A. Oldstone, Argyrios N. Theofilopoulos, Roberto Baccala Viruses have long been implicated in the pathogenesis of autoimmunity, yet their contribution remains circumstantial partly due to the lack of well-documented information on infections prior to autoimmune disease onset. Here, we used the lymphocytic choriomeningitis virus (LCMV) as a model to mechanistically dissect the impact of viral infection on lupus-like autoimmunity. Virus persistence strongly enhanced disease in mice with otherwise weak genetic predisposition but not in highly predisposed or non-autoimmune mice, indicating a synergistic interplay between genetic susceptibility and virus infection. Moreover, endosomal Toll-like receptors (TLRs) and plasmacytoid dendritic cells (pDCs) were both strictly required for disease acceleration, even though LCMV also induces strong TLR-independent type I interferon (IFN-I) production via RNA helicases and MAVS in conventional DCs. These results suggest that LCMV enhances systemic autoimmunity primarily by providing stimulatory nucleic acids for endosomal TLR engagement, whereas overstimulation of the MAVS-dependent cytosolic pathway in the absence of endosomal TLR signaling is insufficient for disease induction.
    Electronic ISSN: 1932-6203
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