The human cytomegalovirus-encoded G protein- coupled receptor UL33 exhibits oncomodulatory properties

Herpesviruses can rewire cellular signaling in host cells by expressing viral G protein- coupled receptors (GPCRs). These viral receptors exhibit homology to human chemokine receptors, but some display constitutive activity and promiscuous G protein coupling. Human cytomegalovirus (HCMV) has been detected in multiple cancers, including glioblastoma, and its genome encodes four GPCRs. One of these receptors, US28, is expressed in glioblastoma and possesses constitutive activity and oncomodulatory properties. UL33, another HCMV-encoded GPCR, also displays constitutive signaling via Gαq, Gαi, and Gαs proteins. However, little is known about the nature and functional effects of UL33-driven signaling. Here, we assessed UL33's signaling repertoire and oncomodulatory potential. UL33 activated multiple proliferative, angiogenic, and inflammatory signaling pathways in HEK293T and U251 glioblastoma cells. Notably, upon infection, UL33 contributed to HCMV-mediated STAT3 activation. Moreover, UL33 increased spheroid growth in vitro and accelerated tumor growth in different in vivo tumor models, including an orthotopic glioblastoma xenograft model. UL33-mediated signaling was similar to that stimulated by US28; however, UL33-induced tumor growth was delayed. Additionally, the spatiotemporal expression of the two receptors only partially overlapped in HCMV-infected glioblastoma cells. In conclusion, our results unveil that UL33 has broad signaling capacity and provide mechanistic insight into its functional effects. UL33, like US28, exhibits oncomodulatory properties, elicited via constitutive activation of multiple signaling pathways. UL33 and US28 might contribute to HCMV's oncomodulatory effects through complementing and converging cellular signaling, and hence UL33 may represent a promising drug target in HCMV-associated malignancies

Frequency of and factors associated with antiseizure medication discontinuation discussions and decisions in patients with epilepsy: a multicenter retrospective chart review

Objective: Guidelines suggest considering antiseizure medication (ASM) discontinuation in patients with epilepsy who become seizure-free. Little is known about how discontinuation decisions are being made in practice. We measured the frequency of, and factors associated with, discussions and decisions surrounding ASM discontinuation. Methods: We performed a multicenter retrospective cohort study at the University of Michigan (UM) and two Dutch centers: Wilhelmina Children's Hospital (WCH) and Stichting Epilepsie Instellingen Nederland (SEIN). We screened all children and adults with outpatient epilepsy visits in January 2015 and included those with at least one visit during the subsequent 2 years where they were seizure-free for at least one year. We recorded whether charts documented (1) a discussion with the patient about possible ASM discontinuation and (2) any planned attempt to discontinue at least one ASM. We conducted multilevel logistic regressions to determine factors associated with each outcome. Results: We included 1058 visits from 463 patients. Of all patients who were seizure-free at least one year, 248/463 (53%) had documentation of any discussion and 98/463 (21%) planned to discontinue at least one ASM. Corresponding frequencies for patients who were seizure-free at least 2 years were 184/285 (65%) and 74/285 (26%). The probability of discussing or discontinuing increased with longer duration of seizure freedom. Still, even for patients who were 10 years seizure-free, our models predicated that in only 49% of visits was a discontinuation discussion documented, and in only 16% of visits was it decided to discontinue all ASMs. Provider-to-provider variation explained 18% of variation in whether patients discontinued any ASM. Significance: Only approximately half of patients with prolonged seizure freedom had a documented discussion about ASM discontinuation. Discontinuation was fairly rare even among low-risk patients. Future work should further explore barriers to and facilitators of counseling and discontinuation attempts

The Extent and Role of Domestic Tourism in a Small Island: The Case of the Isle of Man

This article presents a case concerning microdomestic tourism on the Isle of Man, British Isles. Despite being a small island, research highlights that considerable domestic tourism occurs (referred to as microdomestic tourism to reflect the small island size and distinguish from wider British Isles tourism), including day trips and overnight stays. Participants identified such behavior as touristic, and distinct from other leisure activities. Qualitative interviews with residents explore the nature of and reasons for microdomestic tourism within a small island. Breaks from routine, entertaining friends and family, and exploring less well known landscapes are shown to underpin. Highlighted is that microdomestic tourism has a variety of potential benefits, which may counter some of the restrictions typically faced by a small island community. Support for an otherwise ailing tourism industry may help to protect facilities and infrastructure used by the wider community, maintain tourism capacity, and provide atmosphere attractive to foreign visitors

Variation in seizure risk increases from antiseizure medication withdrawal among patients with well-controlled epilepsy: a pooled analysis

Objective: Guidelines suggest considering antiseizure medication (ASM) discontinuation in seizure-free patients with epilepsy. Past work has poorly explored how discontinuation effects vary between patients. We evaluated (1) what factors modify the influence of discontinuation on seizure risk; and (2) the range of seizure risk increase due to discontinuation across low- versus high-risk patients. Methods: We pooled three datasets including seizure-free patients who did and did not discontinue ASMs. We conducted time-to-first-seizure analyses. First, we evaluated what individual patient factors modified the relative effect of ASM discontinuation on seizure risk via interaction terms. Then, we assessed the distribution of 2-year risk increase as predicted by our adjusted logistic regressions. Results: We included 1626 patients, of whom 678 (42%) planned to discontinue all ASMs. The mean predicted 2-year seizure risk was 43% [95% confidence interval (CI) 39%–46%] for discontinuation versus 21% (95% CI 19%–24%) for continuation. The mean 2-year absolute seizure risk increase was 21% (95% CI 18%–26%). No individual interaction term was significant after correcting for multiple comparisons. The median [interquartile range (IQR)] risk increase across patients was 19% (IQR 14%–24%; range 7%–37%). Results were unchanged when restricting analyses to only the two RCTs. Significance: No single patient factor significantly modified the influence of discontinuation on seizure risk, although we captured how absolute risk increases change for patients that are at low versus high risk. Patients should likely continue ASMs if even a 7% 2-year increase in the chance of any more seizures would be too much and should likely discontinue ASMs if even a 37% risk increase would be too little. In between these extremes, individualized risk calculation and a careful understanding of patient preferences are critical. Future work will further develop a two-armed individualized seizure risk calculator and contextualize seizure risk thresholds below which to consider discontinuation. Plain Language Summary: Understanding how much antiseizure medications (ASMs) decrease seizure risk is an important part of determining which patients with epilepsy should be treated, especially for patients who have not had a seizure in a while. We found that there was a wide range in the amount that ASM discontinuation increases seizure risk—between 7% and 37%. We found that no single patient factor modified that amount. Understanding what a patient's seizure risk might be if they discontinued versus continued ASM treatment is critical to making informed decisions about whether the benefit of treatment outweighs the downsides

Mapping Proprioception across a 2D Horizontal Workspace

Relatively few studies have been reported that document how proprioception varies across the workspace of the human arm. Here we examined proprioceptive function across a horizontal planar workspace, using a new method that avoids active movement and interactions with other sensory modalities. We systematically mapped both proprioceptive acuity (sensitivity to hand position change) and bias (perceived location of the hand), across a horizontal-plane 2D workspace. Proprioception of both the left and right arms was tested at nine workspace locations and in 2 orthogonal directions (left-right and forwards-backwards). Subjects made repeated judgments about the position of their hand with respect to a remembered proprioceptive reference position, while grasping the handle of a robotic linkage that passively moved their hand to each judgement location. To rule out the possibility that the memory component of the proprioceptive testing procedure may have influenced our results, we repeated the procedure in a second experiment using a persistent visual reference position. Both methods resulted in qualitatively similar findings. Proprioception is not uniform across the workspace. Acuity was greater for limb configurations in which the hand was closer to the body, and was greater in a forward-backward direction than in a left-right direction. A robust difference in proprioceptive bias was observed across both experiments. At all workspace locations, the left hand was perceived to be to the left of its actual position, and the right hand was perceived to be to the right of its actual position. Finally, bias was smaller for hand positions closer to the body. The results of this study provide a systematic map of proprioceptive acuity and bias across the workspace of the limb that may be used to augment computational models of sensory-motor control, and to inform clinical assessment of sensory function in patients with sensory-motor deficits

Low-loss waveguides in ultrafast laser-deposited As(2)S(3) chalcogenide films

This paper was published in Journal of the Optical Society of America B and is made available as an electronic reprint with the permission of OSA. The paper can be found at the following URL on the OSA website: http://www.opticsinfobase.org/abstract.cfm?URI=josab-20-9-1844. Systematic or multiple reproduction or distribution to multiple locations via electronic or other means is prohibited and is subject to penalties under law.A. Zakery, Y. Ruan, A. V. Rode, M. Samoc, and B. Luther-Davie

Knowledge of obstetric fistula prevention amongst young women in urban and rural Burkina Faso: a cross-sectional study

Obstetric fistula is a sequela of complicated labour, which, if untreated, leaves women handicapped and socially excluded. In Burkina Faso, incidence of obstetric fistula is 6/10,000 cases amongst gynaecological patients, with more patients affected in rural areas. This study aims to evaluate knowledge on obstetric fistula among young women in a health district of Burkina Faso, comparing rural and urban communities. This cross-sectional study employed multi-stage sampling to include 121 women aged 18-20 years residing in urban and rural communities of Boromo health district. Descriptive statistics and multiple logistic regression analysis were used to compare differences between the groups and to identify predictors of observed knowledge levels. Rural women were more likely to be married (p<0.000) and had higher propensity to teenage pregnancy (p=0.006). The survey showed overall poor obstetric fistula awareness (36%). Rural residents were less likely to have adequate preventive knowledge than urban residents [OR=0.35 (95%-CI, 0.16–0.79)]. This effect was only slightly explained by lack of education [OR=0.41 (95%-CI, 0.18–0.93)] and only slightly underestimated due to previous pregnancy [OR=0.27 (95%-CI, 0.09–0.79)]. Media were the most popular source of awareness amongst urban young women in contrast to their rural counterparts (68% vs. 23%). Most rural young women became ‘aware’ through word-of-mouth (68% vs. 14%). All participants agreed that the hospital was safer for emergency obstetric care, but only 11.0% believed they could face pregnancy complications that would require emergency treatment. There is urgent need to increase emphasis on neglected health messages such as the risks of obstetric fistula. In this respect, obstetric fistula prevention programs need to be adapted to local contexts, whether urban or rural, and multi-sectoral efforts need to be exerted to maximise use of other sectoral resources and platforms, including existing routine health services and schools, to ensure sustainability of health literacy efforts

Lipopolysaccharide glycotyping of clarithromycin-resistant and clarithromycin-susceptible Canadian isolates of Helicobacter pylori

Lipopolysaccharide (LPS) of Helicobacter pylori exhibits several unique structures, such as Lewis (Le) antigens, \u3b1-1, 6-glucan, and DD-heptan. To investigate the relationship between LPS structure and resistance to clarithromycin, 41 Canadian isolates of H. pylori were characterized by whole-cell ELISA (enzyme-linked immunosorbent assay), sugar analysis, immunoblotting, and indirect immunofluorescence. The expression of type 2 Lewis X and (or) Lewis Y antigens was detected in 22 of 23 (95.7%) clarithromycin-resistant and in 14 of 18 (77.7%) clarithromycin-susceptible H. pylori strains (P < 0.05), and 8 isolates co-expressed type 1 and type 2 Le antigens (8/41, 19.5%). A significantly higher frequency of \u3b1-1, 6-glucan (P < 0.01) was detected in clarithromycin-resistant strains than in clarithromycin-susceptible strains (19/23 (82.6%) versus 11/18 (61.1%)). Sugar analysis of selected \u3b1-1, 6-glucan-positive H. pylori strains confirmed that they frequently contained elevated amounts of DD-heptose. Clarithromycin-resistant isolates were also characterized by low expression levels or absence of CagA (17/23, 73.9%). Indirect immunofluorescence studies carried out on selected H. pylori strains with rabbit immune sera specific for \u3b1-1, 6-glucan confirmed broad recognition of \u3b1-1, 6-glucan epitope. The binding was not affected by LPS glycotype of H. pylori isolates examined nor by their CagA status or resistance to clarithromycin. These findings suggest \u3b1-1, 6-glucan as a potential vaccine target, especially in an era of increasing clarithromycin resistance in H. pylori.Peer reviewed: YesNRC publication: Ye

Complementor embeddedness in platform ecosystems : the case of google apps

Platforms and their marketplaces with complementarities are prominent in the software industry. As the proprietary platform itself exhibits elementary or generic functionality, platform owners depend on a complementor ecosystem populated by third-parties. At present, little is known about mechanisms at play in proprietary ecosystems. Addressing this deficiency, this paper investigates the Google Apps ecosystem through statistical and network analysis. Results show that the Google Apps ecosystem is sparsely connected, the majority of complementors develops one application (83%) and does not have visible relationships (73%). Furthermore, there is a positive relationship between the number of applications a complementor develops and the number of relationships it establishes. The research method and results presented can be used by practitioners as a reference to evaluate their structural position in the ecosystem, while it provides researchers with a quantification of ecosystem characteristics