bluuebunny/crossref_metadata_2025_split huggingface dataset:
Summary-data-based Mendelian randomization prioritizes potential druggable targets for multiple sclerosis
Authors: Jacobs Benjamin M , Taylor Thomas , Awad Amine , Baker David , Giovanonni Gavin , Noyce Alastair J , Dobson Ruth 
Published: August 2020

AbstractMultiple sclerosis is a complex autoimmune disease caused by a combination of genetic and environmental factors. Translation of Genome-Wide Association Study findings into therapeutics and effective preventive strategies has been limited to date. We used summary-data-based Mendelian randomization to synthesize findings from public expression quantitative trait locus, methylation quantitative trait locus and Multiple Sclerosis Genome-Wide Association Study datasets. By correlating the effects of methylation on multiple sclerosis, methylation on expression and expression on multiple sclerosis susceptibility, we prioritize genetic loci with evidence of influencing multiple sclerosis susceptibility. We overlay these findings onto a list of ‘druggable’ genes, i.e. genes which are currently, or could theoretically, be targeted by therapeutic compounds. We use GeNets and search tool for the retrieval of interacting genes/proteins to identify protein–protein interactions and druggable pathways enriched in our results. We extend these findings to a model of Epstein-Barr virus-infected B cells, lymphoblastoid cell lines. We conducted a systematic review of prioritized genes using the Open Targets platform to identify completed and planned trials targeting prioritized genes in multiple sclerosis and related disease areas. Expression of 45 genes in peripheral blood was strongly associated with multiple sclerosis susceptibility (False discovery rate 0.05). Of these 45 genes, 20 encode a protein which is currently targeted by an existing therapeutic compound. These genes were enriched for Gene Ontology terms pertaining to immune system function and leucocyte signalling. We refined this prioritized gene list by restricting to loci where CpG site methylation was associated with multiple sclerosis susceptibility, with gene expression and where expression was associated with multiple sclerosis susceptibility. This approach yielded a list of 15 prioritized druggable target genes for which there was evidence of a pathway linking methylation, expression and multiple sclerosis. Five of these 15 genes are targeted by existing drugs and three were replicated in a smaller expression Quantitative Trait Loci dataset (CD40, MERTK and PARP1). In lymphoblastoid cell lines, this approach prioritized 7 druggable gene targets, of which only one was prioritized by the multi-omic approach in peripheral blood (FCRL3). Systematic review of Open Targets revealed multiple early-phase trials targeting 13/20 prioritized genes in disorders related to multiple sclerosis. We use public datasets and summary-data-based Mendelian randomization to identify a list of prioritized druggable genetic targets in multiple sclerosis. We hope our findings could be translated into a platform for developing targeted preventive therapies.
Prophylactic Negative-pressure Wound Therapy Prevents Surgical Site Infection in Abdominal Surgery: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials and Observational Studies
Authors: Meyer Jeremy , Roos Elin , Abbassi Ziad , Buchs Nicolas C , Ris Frédéric , Toso Christian 
Published: August 2020

Abstract

Background
Prevention of surgical site infection (SSI) is a public health challenge. Our objective was to determine if prophylactic negative-pressure wound therapy (pNPWT) allows preventing SSI after laparotomy.

Methods
Medline, Embase, and Web of Science were searched on 6 October 2019 for original studies reporting the incidences of SSI in patients undergoing open abdominal surgery with and without pNPWT. Risk differences (RDs) between control and pNPWT patients and risk ratios (RRs) for SSI were obtained using random-effects models.

Results
Twenty-one studies (2930 patients, 5 randomized controlled trials [RCTs], 16 observational studies) were retained for the analysis. Pooled RD between patients with and without pNPWT was −12% (95% confidence interval [CI], −17% to −8%; I2 = 57%; P &lt; .00001) in favor of pNPWT. That risk difference was −12% (95% CI, −22% to −1%; I2 = 69%; P = .03) when pooling only RCTs (792 patients). pNPWT was protective against the incidence of SSI with a RR of 0.53 (95% CI, .40–.71; I2 = 56%; P &lt; .0001). The effect on pNPWT was more pronounced in studies with an incidence of SSI ≥20% in the control arm. The preventive effect of pNPWT on SSI remained after correction for potential publication bias. However, when pooling only high-quality observational studies (642 patients) or RCTs (527 patients), significance was lost.

Conclusions
Existing studies suggest that pNPWT on closed wounds is protective against the occurrence of SSI in abdominal surgery, but these findings need to be confirmed by more high-quality evidence, preferentially in subgroups of patients with an incidence of SSI ≥20% in the control arm.
A Randomized Phase 2 Study of VT-1161 for the Treatment of Acute Vulvovaginal Candidiasis
Authors: Brand Stephen R , Sobel Jack D , Nyirjesy Paul , Ghannoum Mahmoud A , Schotzinger Robert J , Degenhardt Thorsten P 
Published: August 2020

Abstract

Background
Acute vulvovaginal candidiasis (VVC) is common among women, but current azole antifungal treatments are often associated with safety and resistance issues. VT-1161 (oteseconazole) is an oral agent with increased selectivity for fungal CYP51. In this phase 2 clinical study, we evaluated the efficacy and safety of VT-1161 vs fluconazole in participants with moderate to severe acute VVC.

Methods
Participants presenting with an acute episode of VVC (n = 55) were randomized to receive VT-1161 300 mg once daily (q.d.) for 3 days, 600 mg q.d. for 3 days, or 600 mg twice daily (b.i.d.) for 3 days or to receive a single dose of fluconazole 150 mg (FDA-approved dose to treat acute VVC). Participants were followed for 6 months. The primary outcome was the proportion of participants with therapeutic (clinical and mycological) cure at day 28.

Results
A larger proportion of participants in the per-protocol population experienced therapeutic cure in the VT-1161 300 mg q.d. (75.0%), VT-1161 600 mg q.d. (85.7%), and VT-1161 600 mg b.i.d. (78.6%) groups vs the fluconazole group (62.5%); differences were not statistically significant. At 3 and 6 months, no participants in the VT-1161 groups vs 28.5% and 46.1% in the fluconazole group, respectively, had evidence of mycological recurrence. No serious adverse events or treatment-emergent adverse events leading to discontinuation were reported.

Conclusions
The majority of participants across all treatment groups achieved therapeutic cure at day 28. VT-1161 was well tolerated at all dose levels through 6 months of follow-up.

Clinical Trials Registration
NCT01891331.
Immuno-pharmacokinetics of Meglumine Antimoniate in Patients With Cutaneous Leishmaniasis Caused byLeishmania(Viannia)
Authors: Gómez María Adelaida , Navas Adriana , Prieto Miguel Dario , Giraldo-Parra Lina , Cossio Alexandra , Alexander Neal , Gore Saravia Nancy 
Published: August 2020

AbstractBackgroundControl of cutaneous leishmaniasis (CL) relies on chemotherapy, yet gaps in our understanding of the determinants of therapeutic outcome impede optimization of antileishmanial drug regimens. Pharmacodynamic (PD) parameters of antimicrobials are based on the relationship between drug concentrations/exposure and microbial kill. However, viable Leishmania persist in a high proportion of individuals despite clinical resolution, indicating that determinants other than parasite clearance are involved in drug efficacy.MethodsIn this study, the profiles of expression of neutrophils, monocytes, Th1 and Th17 gene signatures were characterized in peripheral blood mononuclear cells (PBMCs) during treatment with meglumine antimoniate (MA) and clinical cure of human CL caused by Leishmania (Viannia). We explored relationships of immune gene expression with plasma and intracellular antimony (Sb) concentrations.ResultsOur findings show a rapid and orchestrated modulation of gene expression networks upon exposure to MA. We report nonlinear pharmacokinetic/pharmacodynamic (PK/PD) relationships of Sb and gene expression dynamics in PBMCs , concurring with a time lag in the detection of intracellular drug concentrations and with PK evidence of intracellular Sb accumulation.ConclusionsOur results quantitatively portray the immune dynamics of therapeutic healing, and provide the knowledge base for optimization of antimonial drug treatments, guiding the selection and/or design of targeted drug delivery systems and strategies for targeted immunomodulation.
Marvels and Commonplaces in the Elizabethan Anthologies
Authors: Tregear Ted 
Published: August 2020

Abstract
In a brief essay on Cato the Younger, Montaigne draws together five excerpts from Latin verse in Cato's honour; by the time he returned to the essay in his final years, those excerpts elicited some of the author's richest remarks on poetry and the poetic sublime. This essay argues that the anthology, in its various shapes and forms, offered early modern readers a way of doing literary criticism. Taking its cue from Montaigne's essay, it focuses on a number of English anthologies, associated with John Bodenham, and often known as the ‘Wits’ series, printed at around the turn of the seventeenth century. It argues that the commonplace-book structure of these volumes acted as a spur to detailed stylistic analysis. Anthologies encouraged their readers to compare poets with one another, working out what they had in common, and what made each one distinct; in this, they fostered the sort of critical scrutiny discussed in Scaliger's Poetics, and put into practice in the theatrical exchanges of the ‘Poets' War’. But as in Montaigne's case, they could also spark reflections about those verses that lay beyond criticism's reach, in the numinous realm of the sublime.
Extraintestinal Manifestations and Other Comorbidities in Ulcerative Colitis and Crohn Disease: A Danish Nationwide Registry Study 2003–2016
Authors: Vadstrup Kasper , Alulis Sarah , Borsi Andras , Jørgensen Tine Rikke , Nielsen Agnete , Munkholm Pia , Qvist Niels 
Published: August 2020

AbstractBackgroundExtraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD) may be a frequent complication to an underlying abnormal immune response. This study investigated the occurrence of EIMs in Crohn disease (CD) and ulcerative colitis (UC) patients using population-based data in Denmark from 2003 to 2016.MethodsIn this national registry-based study, incident CD and UC patients between 2003 and 2015 were matched on age and gender with non-IBD controls and followed until 2016. The selected EIMs for this study included 51 different diagnoses divided into biological systems of diseases, which were tested for differences in the timing and occurrence of EIMs.ResultsThe study cohort included 10,302 patients with CD and 22,144 patients with UC. The highest risk of patients experiencing EIM/comorbidities for the first time before their IBD diagnosis was in the skin and intestinal tract systems. For CD, the odds ratio of having an EIM before or after IBD diagnosis, as compared with controls, was significant in the skin, intestinal tract, hepatopancreatobiliary, musculoskeletal, ocular, renal, and respiratory systems. For UC, the risks were similar before and after UC diagnosis, apart from the nervous system where the odds ratio was significantly higher before the diagnosis of UC, and significantly lower after diagnosis for diseases in the ocular system.ConclusionsEIMs in CD and UC patients may also precede their IBD diagnosis. These findings may indicate a significant diagnostic delay of CD and UC, and the occurrence of known EIMs should prompt physicians to look for patients possibly having underlying IBD.
The JAK1/3 Inhibitor to Tofacitinib Suppresses T Cell Homing and Activation in Chronic Intestinal Inflammation
Authors: Gerlach Katharina , Lechner Kristina , Popp Vanessa , Offensperger Laura , Zundler Sebastian , Wiendl Maximilian , Becker Emily , Atreya Raja , Rath Timo , Neurath Markus F , Weigmann Benno 
Published: August 2020

AbstractBackground and AimsThe molecular mechanism of action of the Janus kinase [JAK] inhibitor tofacitinib is poorly understood.MethodsHere we analysed the inhibitory effect of tofacitinib on mucosal and blood T cells from patients with ulcerative colitis [UC]. Furthermore, tofacitinib treatment was analysed in experimental colitis models and wound healing. Additionally, tofacitinib effects were analysed in bioassays.ResultsTofacitinib significantly reduced T cell-derived inflammatory cytokine production [Th2, Th9, Th17] in patients with active UC. Additionally, impaired expression of the homing receptors alpha4/beta1 and alpha4/beta7, as well as reduced gut homing capacity of T cells in a humanised mouse model of colitis, were observed. Tofacitinib suppressed acute and chronic oxazolone colitis, compared with untreated wild-type mice, associated with downregulation of cytokines produced by Th2, Th9, and Th17 cells. Functionally, tofacitinib induced apoptosis of intestinal epithelial cells and prevented mucosal wound healing in vivo at higher concentration. Thus, our findings suggest that tofacitinib is quite effective in protecting from colitis, by inhibition of a bundle of T cell-derived cytokines like IL-5, IL-6, IL-9, IL-13, and IL-17A.ConclusionsApplication of tofacitinib emerges as an attractive concept for treatment of chronic intestinal inflammation at lower concentrations, whereas higher concentrations require attention due to prolonged wound healing.PodcastThis article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast
Impact of Hemlock Woolly Adelgid (Hemiptera: Adelgidae) Infestation on the Jasmonic Acid-Elicited Defenses of Tsuga canadensis (Pinales: Pinaceae)
Authors: Rigsby Chad M , Kinahan Ian G , May Amelia , Kostka Amy , Houseman Nick , Savage Suzanne K , Whitney Elizabeth R , Preisser Evan L 
Published: August 2020

AbstractHemlock woolly adelgid is an invasive piercing-sucking insect in eastern North America, which upon infestation of its main host, eastern hemlock (‘hemlock’), improves attraction and performance of folivorous insects on hemlock. This increased performance may be mediated by hemlock woolly adelgid feeding causing antagonism between the the jasmonic acid and other hormone pathways. In a common garden experiments using hemlock woolly adelgid infestation and induction with methyl jasmonate (MeJA) and measures of secondary metabolite contents and defense-associated enzyme activities, we explored the impact of hemlock woolly adelgid feeding on the local and systemic induction of jasmonic acid (JA)-elicited defenses. We found that in local tissue hemlock woolly adelgid or MeJA exposure resulted in unique induced phenotypes, whereas the combined treatment resulted in an induced phenotype that was a mixture of the two individual treatments. We also found that if the plant was infested with hemlock woolly adelgid, the systemic response of the plant was dominated by hemlock woolly adelgid, regardless of whether MeJA was applied. Interestingly, in the absence of hemlock woolly adelgid, hemlock plants had a very weak systemic response to MeJA. We conclude that hemlock woolly adelgid infestation prevents systemic induction of JA-elicited defenses. Taken together, compromised local JA-elicited defenses combined with weak systemic induction could be major contributors to increased folivore performance on hemlock woolly adelgid-infested hemlock.
The Attraction of Amazonian Dung Beetles (Coleoptera: Scarabaeidae: Scarabaeinae) to the Feces of Omnivorous Mammals Is Dependent on Their Diet: Implications for Ecological Monitoring
Authors: Ferreira Kleyton R , Puker Anderson , Correa César M A 
Published: August 2020

Abstract
The immense sampling effort used in ecological research on dung beetles (Coleoptera: Scarabaeidae: Scarabaeinae) has required large amounts of human feces to conduct experiments in the field. Thus, the amount of human feces available can be an important limiting factor for research. Therefore, dung from large omnivorous mammals, such as pig, has been used to reduce this limitation. Here, we evaluated how the type of diet can influence the attractiveness of omnivorous-mammal feces to Amazonian dung beetles. We sampled dung beetles in 10 fragments of Amazon rainforest in July 2018 (dry season) and March 2019 (rainy season), using pitfall traps baited with swill pig dung (household waste-based diet), grain pig dung (maize+soybean-based diet), and human feces (control) in Juína, Mato Grosso, Brazil. In all, 2,080 individuals from 51 species of dung beetles were collected. Between the pig dung evaluated, higher total abundance and species richness was captured with grain pig dung. However, the species composition and community structure were similar between pig dung types. Additionally, grain pig dung captured total species richness, species composition, and structure similar to that for human feces. Thus, although grain pig dung did not sample total abundance similar to human feces, this type of dung can be efficient for an accurate survey of the total species richness, species composition, and structure of dung beetles in the Amazon rainforest.
The pandemic predominantly hits poor neighbourhoods? SARS-CoV-2 infections and COVID-19 fatalities in German districts
Authors: Plümper Thomas , Neumayer Eric 
Published: August 2020

AbstractBackgroundReports from the UK and the USA suggest that coronavirus disease 2019 (COVID-19) predominantly affects poorer neighbourhoods. This article paints a more complex picture by distinguishing between a first and second phase of the pandemic. The initial spread of infections and its correlation with socio-economic factors depends on how the virus first entered a country. The second phase of the pandemic begins when individuals start taking precautionary measures and governments implement lockdowns. In this phase, the spread of the virus depends on the ability of individuals to socially distance themselves, which is to some extent socially stratified.MethodsWe analyze the geographical distribution of known cumulative cases and fatalities per capita in an ecological analysis across local districts in Germany distinguishing between the first and the second phase of the pandemic.ResultsIn Germany, the virus first entered via individuals returning from skiing in the Alps and other international travel. In this first phase, we find a positive association between the wealth of a district and infection rates and a negative association with indicators of social deprivation. During the second phase and controlling for path dependency, districts with a higher share of university-educated employees record fewer new infections and deaths and richer districts record fewer deaths, districts with a higher unemployment rate record more deaths.ConclusionsThe social stratification of COVID-19 changes substantively across the two phases of the pandemic in Germany. Only in the second phase and controlling for temporal dependence does COVID-19 predominantly hit poorer districts.
Understanding the Metabolic Capacity of Antarctic Fishes to Acclimate to Future Ocean Conditions
Authors: Todgham Anne E , Mandic Milica 
Published: August 2020

SynopsisAntarctic fishes have evolved under stable, extreme cold temperatures for millions of years. Adapted to thrive in the cold environment, their specialized phenotypes will likely render them particularly susceptible to future ocean warming and acidification as a result of climate change. Moving from a period of stability to one of environmental change, species persistence will depend on maintaining energetic equilibrium, or sustaining the increased energy demand without compromising important biological functions such as growth and reproduction. Metabolic capacity to acclimate, marked by a return to metabolic equilibrium through physiological compensation of routine metabolic rate (RMR), will likely determine which species will be better poised to cope with shifts in environmental conditions. Focusing on the suborder Notothenioidei, a dominant group of Antarctic fishes, and in particular four well-studied species, Trematomus bernacchii, Pagothenia borchgrevinki, Notothenia rossii, and N. coriiceps, we discuss metabolic acclimation potential to warming and CO2-acidification using an integrative and comparative framework. There are species-specific differences in the physiological compensation of RMR during warming and the duration of acclimation time required to achieve compensation; for some species, RMR fully recovered within 3.5 weeks of exposure, such as P. borchgrevinki, while for other species, such as N. coriiceps, RMR remained significantly elevated past 9 weeks of exposure. In all instances, added exposure to increased PCO2, further compromised the ability of species to return RMR to pre-exposure levels. The period of metabolic imbalance, marked by elevated RMR, was underlined by energetic disturbance and elevated energetic costs, which shifted energy away from fitness-related functions, such as growth. In T. bernacchii and N. coriiceps, long duration of elevated RMR impacted condition factor and/or growth rate. Low growth rate can affect development and ultimately the timing of reproduction, severely compromising the species’ survival potential and the biodiversity of the notothenioid lineage. Therefore, the ability to achieve full compensation of RMR, and in a short-time frame, in order to avoid long term consequences of metabolic imbalance, will likely be an important determinant in a species’ capacity to persist in a changing environment. Much work is still required to develop our understanding of the bioenergetics of Antarctic fishes in the face of environmental change, and a targeted approach of nesting a mechanistic focus in an ecological and comparative framework will better aid our predictions on the effect of global climate change on species persistence in the polar regions.
Wall-Crossing for Newton–Okounkov Bodies and the Tropical Grassmannian
Authors: Escobar Laura , Harada Megumi 
Published: August 2020

Abstract
Tropical geometry and the theory of Newton–Okounkov bodies are two methods that produce toric degenerations of an irreducible complex projective variety. Kaveh and Manon showed that the two are related. We give geometric maps between the Newton–Okounkov bodies corresponding to two adjacent maximal-dimensional prime cones in the tropicalization of $X$. Under a technical condition, we produce a natural “algebraic wall-crossing” map on the underlying value semigroups (of the corresponding valuations). In the case of the tropical Grassmannian $Gr(2,m)$, we prove that the algebraic wall-crossing map is the restriction of a geometric map. In an appendix by Nathan Ilten, he explains how the geometric wall-crossing phenomenon can also be derived from the perspective of complexity-one $T$-varieties; Ilten also explains the connection to the “combinatorial mutations” studied by Akhtar–Coates–Galkin–Kasprzyk.