bluuebunny/crossref_metadata_2025_split huggingface dataset:
Projected costs associated with school-based screening to inform deployment of Dengvaxia: Vietnam as a case study
Authors: Turner Hugo C , Wills Bridget A , Rahman Motiur , Quoc Cuong Hoang , Thwaites Guy E , Boni Maciej F , Clapham Hannah E 
Published: June 2018

Abstract

Background
After new analysis, Sanofi Pasteur now recommends their dengue vaccine (Dengvaxia) should only be given to individuals previously infected with dengue and the World Health Organization’s recommendations regarding its use are currently being revised. As a result, the potential costs of performing large-scale individual dengue screening and/or dengue serosurveys have become an important consideration for decision making by policymakers in dengue-endemic areas.

Methods
We used an ingredients-based approach to estimate the financial costs for conducting both a school-based dengue serosurvey and school-based individual dengue screening within a typical province in Vietnam, using an existing commercial indirect immunoglobulin G enzyme-linked immunosorbent assay kit. This costing is hypothetical and based on estimates regarding the resources that would be required to perform such activities.

Results
We estimated that performing a school-based individual screening of 9-year-olds would cost US$9.25 per child tested or US$197,827 in total for a typical province. We also estimated that a school-based serosurvey would cost US$10,074, assuming one class from each of the grades that include 8- to 11-year-olds are sampled at each of the 12 selected schools across the province.

Conclusions
The study indicates that using this vaccine safely on a large-scale will incur noteworthy operational costs. It is crucial that these be considered in future cost-effectiveness analyses informing how and where the vaccine is deployed.
Outcomes After Minimally-invasive Versus Open Pancreatoduodenectomy
Authors: Klompmaker Sjors , van Hilst Jony , Wellner Ulrich F. , Busch Olivier R. , Coratti Andrea , D’Hondt Mathieu , Dokmak Safi , Festen Sebastiaan , Kerem Mustafa , Khatkov Igor , Lips Daan J. , Lombardo Carlo , Luyer Misha , Manzoni Alberto , Molenaar Izaäk Q. , Rosso Edoardo , Saint-Marc Olivier , Vansteenkiste Franky , Wittel Uwe A. , Bonsing Bert , Groot Koerkamp Bas , Abu Hilal Mohammed , Fuks David , Poves Ignasi , Keck Tobias , Boggi Ugo , Besselink Marc G. 
Published: June 2018

Objective:
To assess short-term outcomes after minimally invasive (laparoscopic, robot-assisted, and hybrid) pancreatoduodenectomy (MIPD) versus open pancreatoduodenectomy (OPD) among European centers.

Background:
Current evidence on MIPD is based on national registries or single expert centers. International, matched studies comparing outcomes for MIPD and OPD are lacking.

Methods:
Retrospective propensity score matched study comparing MIPD in 14 centers (7 countries) performing ≥10 MIPDs annually (2012–2017) versus OPD in 53 German/Dutch surgical registry centers performing ≥10 OPDs annually (2014–2017). Primary outcome was 30-day major morbidity (Clavien-Dindo ≥3).

Results:
Of 4220 patients, 729/730 MIPDs (412 laparoscopic, 184 robot-assisted, and 130 hybrid) were matched to 729 OPDs. Median annual case-volume was 19 MIPDs (interquartile range, IQR 13–22), including the first MIPDs performed in 10/14 centers, and 31 OPDs (IQR 21–38). Major morbidity (28% vs 30%, P = 0.526), mortality (4.0% vs 3.3%, P = 0.576), percutaneous drainage (12% vs 12%, P = 0.809), reoperation (11% vs 13%, P = 0.329), and hospital stay (mean 17 vs 17 days, P > 0.99) were comparable between MIPD and OPD. Grade-B/C postoperative pancreatic fistula (POPF) (23% vs 13%, P < 0.001) occurred more frequently after MIPD. Single-row pancreatojejunostomy was associated with POPF in MIPD (odds ratio, OR 2.95, P < 0.001), but not in OPD. Laparoscopic, robot-assisted, and hybrid MIPD had comparable major morbidity (27% vs 27% vs 35%), POPF (24% vs 19% vs 25%), and mortality (2.9% vs 5.2% vs 5.4%), with a fewer conversions in robot-assisted- versus laparoscopic MIPD (5% vs 26%, P < 0.001).

Conclusions:
In the early experience of 14 European centers performing ≥10 MIPDs annually, no differences were found in major morbidity, mortality, and hospital stay between MIPD and OPD. The high rates of POPF and conversion, and the lack of superior outcomes (ie, hospital stay, morbidity) could indicate that more experience and higher annual MIPD volumes are needed.
Parasite insight: assessing fitness costs, infection risks and foraging benefits relating to gastrointestinal nematodes in wild mammalian herbivores
Authors: Coulson Graeme , Cripps Jemma K. , Garnick Sarah , Bristow Verity , Beveridge Ian 
Published: June 2018

Mammalian herbivores are typically infected by parasitic nematodes, which are acquired through direct, faecal–oral transmission. These parasites can cause significant production losses in domestic livestock, but much less is known about impacts on wild mammalian hosts. We review three elements of parasitism from the host's perspective: fitness costs of infection, risks of infection during foraging and benefits of nutritious pasture. The majority of wildlife studies have been observational, but experimental manipulation is increasing. Treatment with anthelmintics to manipulate parasite load has revealed varied impacts of parasites on fitness variables across host species, but has not produced consistent evidence for parasite-induced anorexia or impaired body condition. Some experimental studies of infection risk have manipulated faecal contamination and detected faecal avoidance by hosts. Only two field studies have explored the trade-off between infection risk and nutritional benefit generated by avoidance of contaminated patches. Overall, field studies of costs, risks and benefits of the host–parasite relationship are limited and few have examined more than one of these elements. Parasitism has much in common with predation, and future insights into anti-parasite responses by wild hosts could be gained from the conceptual and technical developments in research on anti-predator behaviour.This article is part of the Theo Murphy meeting issue ‘Evolution of pathogen and parasite avoidance behaviours’.
Ectoparasite defence in humans: relationships to pathogen avoidance and clinical implications
Authors: Kupfer Tom R. , Fessler Daniel M. T. 
Published: June 2018

Currently, disgust is regarded as the main adaptation for defence against pathogens and parasites in humans. Disgust's motivational and behavioural features, including withdrawal, nausea, appetite suppression and the urge to vomit, defend effectively against ingesting or touching sources of pathogens. However, ectoparasites do not attack their hosts via ingestion, but rather actively attach themselves to the body surface. Accordingly, by itself, disgust offers limited defence against ectoparasites. We propose that, like non-human animals, humans have a distinct ectoparasite defence system that includes cutaneous sensory mechanisms, itch-generation mechanisms and grooming behaviours. The existence of adaptations for ectoparasite defence is supported by abundant evidence from non-human animals, as well as more recent evidence concerning human responses to ectoparasite cues. Several clinical disorders may be dysfunctions of the ectoparasite defence system, including some that are pathologies of grooming, such as skin picking and trichotillomania, and others, such as delusory parasitosis and trypophobia, which are pathologies of ectoparasite detection. We conclude that future research should explore both distinctions between, and overlap across, ectoparasite defence systems and pathogen avoidance systems, as doing so will not only illuminate proximate motivational systems, including disgust, but may also reveal important clinical and social consequences.This article is part of the Theo Murphy meeting issue ‘Evolution of pathogen and parasite avoidance behaviours'.
Machine learning for randomised controlled trials: identifying treatment effectheterogeneity with strict control of type I error
Authors: Holmes Chris C. , Watson James A. 
Published: June 2018

AbstractBackgroundIt is widely acknowledged that retrospective exploratory analyses of randomised controlled trials (RCTs) seeking to identify treatment effect heterogeneity (TEH) are prone to bias and false positives. Yet the increasing availability of multiple data modalities on subjects and the desire to learn all we can from trial participants motivates the inclusion of such analyses within RCTs. Coupled to this, widespread advances in AI and machine learning (ML) methods hold great potential to utilise such data to characterise subjects exhibiting heterogeneous treatment response.MethodsWe present new learning strategies for RCT ML discovery methods that ensure strict control of the false positive reporting rate at a pre-specified level. Our approach uses randomised data partitioning and statistical or ML based prediction on held-out data. This can test for both crossover and non-crossover TEH. The former is done via a two-sample hypothesis test measuring overall predictive performance of the ML method. The latter is done via ‘stacking’ the ML predictors alongside a classical statistical model to formally test the added benefit of the ML algorithm. An adaptation of recent statistical theory allows for the construction of a valid aggregate p-value. This learning strategy is agnostic to the choice of ML method.ResultsWe demonstrate our approach with a re-analysis of the SEAQUAMAT trial. We find no evidence for any crossover subgroup who would benefit from a change in treatment from the current standard-of-care, artesunate, but strong evidence for significant noncrossover TEH within the artesunate treatment group. We find that artesunate provides a differential benefit to patients with high numbers of circulating ring stage parasites.ConclusionsOur ML approach combined with the use of computational notebooks and version control can improve the robustness and transparency of RCT exploratory analyses. The methods allow researchers to apply the latest ML techniques safe in the knowledge that any declared associations are statistically significant at a user defined level.
Isolating and Quantifying the Role of Developmental Noise in Generating Phenotypic Variation
Authors: Kiskowski Maria , Glimm Tilmann , Moreno Nickolas , Gamble Tony , Chiari Ylenia 
Published: June 2018

AbstractPhenotypic variation in organisms is typically attributed to genotypic variation, environmental variation, and their interaction. Developmental noise, which arises from stochasticity in cellular and molecular processes occurring during development when genotype and environment are fixed, also contributes to phenotypic variation. The potential influence of developmental noise is likely underestimated in studies of phenotypic variation due to intrinsic mechanisms within organisms that stabilize phenotypes and decrease variation. Since we are just beginning to appreciate the extent to which phenotypic variation due to stochasticity is potentially adaptive, the contribution of developmental noise to phenotypic variation must be separated and measured to fully understand its role in evolution. Here, we show that phenotypic variation due to genotype and environment, versus the contribution of developmental noise, can be distinguished for leopard gecko (Eublepharis macularius) head color patterns using mathematical simulations that model the role of random variation (corresponding to developmental noise) in patterning. Specifically, we modified the parameters of simulations corresponding to genetic and environmental variation to generate the full range of phenotypic variation in color pattern seen on the heads of eight leopard geckos. We observed that over the range of these parameters, the component of variation due to genotype and environment exceeds that due to developmental noise in the studied gecko cohort. However, the effect of developmental noise on patterning is also substantial. This approach can be applied to any regular morphological trait that results from self-organized processes such as reaction-diffusion mechanisms, including the frequently found striped and spotted patterns of animal pigmentation patterning, patterning of bones in vertebrate limbs, body segmentation in segmented animals. Our approach addresses one of the major goals of evolutionary biology: to define the role of stochasticity in shaping phenotypic variation.
Image Scanning Microscopy with Single-Photon Detector Array
Authors: Castello Marco , Tortarolo Giorgio , Buttafava Mauro , Deguchi Takahiro , Villa Federica , Koho Sami , Bianchini Paolo , Sheppard Colin J. R. , Diaspro Alberto , Tosi Alberto , Vicidomini Giuseppe 
Published: June 2018

Image scanning microscopy (ISM) improves the spatial resolution of conventional confocal laser-scanning microscopy (CLSM), but current implementations reduce versatility and restrict its combination with fluorescence spectroscopy techniques, such as fluorescence lifetime. Here, we describe a natural design of ISM based on a fast single-photon detector array, which allows straightforward upgrade of an existing confocal microscope, without compromising any of its functionalities. In contrast to all-optical ISM implementations, our approach provides access to the raw scanned images, opening the way to adaptive reconstruction methods, capable of considering different imaging conditions and distortions. We demonstrate its utility in the context of fluorescence lifetime, deep, multicolor and live-cell imaging. This implementation will pave the way for a transparent and massive transition from conventional CLSM to ISM.confocal microscopy | time-resolved spectroscopy | image scanning microscopy | single-photon detector array
pH-mediated inhibition of a bumble bee parasite by an intestinal symbiont
Authors: Palmer-Young Evan C , Raffel Thomas R , McFrederick Quinn S 
Published: June 2018

ABSTRACTNon-pathogenic microbes can provide multiple benefits to their hosts, including pathogen inhibition. Gut symbionts can augment resistance to pathogens by stimulating host immune responses, competing for space and nutrients, or producing antimicrobial metabolites. The gut microbiota of social bees, which pollinate many crops and wildflowers, has demonstrated benefits against diverse infections and might help protect against pathogen-related declines. The bumble bee gut microbiota, consisting chiefly of five taxa common to corbiculate bees, has been shown to enhance resistance to the trypanosomatid parasiteCrithidia bombi. Specifically, infection intensity was negatively correlated with abundance ofLactobacillus“Firm-5” bacteria. However, the mechanism underlying this relationship remains unknown. We tested the hypothesis that the Firm-5 bacteriumLactobacillus bombicola, which produces lactic acid, inhibitsC. bombivia a pH-mediated effect.Consistent with our hypothesis,Lactobacillus bombicolaspent medium inhibitedC. bombigrowth via a reduction in pH that was both necessary and sufficient for inhibition. Inhibition of all parasite strains occurred within the pH range previously observed in honey bee guts, though sensitivity to acidity varied among parasite strains. Spent medium was slightly more potent than HCl, D-, and L-lactic acids for a given pH, suggesting that other metabolites also contribute to inhibitory effects. Our results implicate symbiont-mediated reduction in gut pH as a key determinant of trypanosomatid infection in bees. Future investigation intoin vivoeffects of gut microbial composition on pH and infection intensity would help determine the relevance of these findings for bees threatened by trypanosomatids.ImportancePollinators such as honey and bumble bees provide services to plants in agricultural and wild ecosystems, but both wild and managed bees are threatened by infection-related declines. The symbiotic gut microbiota of bees provides a naturally occurring defense against infection. For example, the bumble bee microbiota reduces infection with trypanosomatid parasites, but how inhibition occurs remains unknown. We show that the acidic spent medium from a common bumble bee gut symbiont,Lactobacillus bombicola,inhibitsin vitrogrowth of the trypanosomatid gut parasite,Crithidia bombi.The acidity of the spent medium was both necessary and sufficient for parasite inhibition. Inhibitory pH values were within the range documented in honey bee guts, suggesting that pH-mediated parasite inhibition is plausible in live bees. Results suggest that production of acids by sugar-fermenting symbionts confers pH-mediated resistance to infection in bees, whereas depletion of core microbiota could result in low-acid conditions that favor parasite growth.
Cross-feeding between Bifidobacterium infantis and Anaerostipes caccae on lactose and human milk oligosaccharides
Authors: Chia Loo Wee , Mank Marko , Blijenberg Bernadet , Bongers Roger S. , Aalvink Steven , Limpt Kees van , Wopereis Harm , Tims Sebastian , Stahl Bernd , Belzer Clara , Knol Jan 
Published: June 2018

AbstractThe establishment of the gut microbiota immediately after birth is a dynamic process that may impact lifelong health. At this important developmental stage in early life, human milk oligosaccharides (HMOS) serve as specific substrates to promote the growth of gut microbes, particularly the group of Actinobacteria (bifidobacteria). Later in life, this shifts to the colonisation of Firmicutes and Bacteroidetes, which generally dominate the human gut throughout adulthood. The well-orchestrated transition is important for health, as an aberrant microbial composition and/or SCFA production are associated with colicky symptoms and atopic diseases in infants. Here, we study the trophic interactions between an HMOS-degrader, Bifidobacterium longum subsp. infantis and the butyrogenic Anaerostipes caccae using carbohydrate substrates that are relevant in this early life period, i.e. lactose and HMOS. Mono-and co-cultures of these bacterial species were grown at pH 6.5 in anaerobic bioreactors supplemented with lactose or total human milk carbohydrates (containing both lactose and HMOS). A cac was not able to grow on these substrates except when grown in co-culture with B. inf, leading concomitant butyrate production. Cross-feeding was observed, in which A. cac utilised the liberated monosaccharides as well as lactate and acetate produced by B. inf. This microbial cross-feeding is indicative of the key ecological role of bifidobacteria in providing substrates for other important species to colonise the infant gut. The symbiotic relationship between these key species contributes to the gradual production of butyrate early in life that could be important for host-microbial cross-talk and gut maturation.ImportanceThe establishment of a healthy infant gut microbiota is crucial for the immune, metabolic and neurological development of infants. Recent evidence suggests that an aberrant gut microbiota early in life could lead to discomfort and predispose infants to the development of immune related diseases. This paper addresses the ecosystem function of two resident microbes of the infant gut. The significance of this research is the proof of cross-feeding interactions between HMOS-degrading bifidobacteria and a butyrate-producing microorganism. Bifidobacteria in the infant gut that support the growth and butyrogenesis of butyrate-producing bacteria, could orchestrated an important event of maturation for both the gut ecosystem and physiology of infant.
Innate visual preferences and behavioral flexibility inDrosophila
Authors: Grabowska Martyna J. , Steeves James , Alpay Julius , Poll Matthew Van De , Ertekin Deniz , Swinderen Bruno van 
Published: June 2018

AbstractVisual decision-making in animals is influenced by innate preferences as well as experience. Interaction between hard-wired responses and changing motivational states determines whether a visual stimulus is attractive, aversive, or neutral. It is however difficult to separate the relative contribution of nature versus nurture in experimental paradigms, especially for more complex visual parameters such as the shape of objects. We used a closed-loop virtual reality paradigm for walkingDrosophilaflies to uncover innate visual preferences for the shape and size of objects, in a recursive choice scenario allowing the flies to reveal their visual preferences over time. We found thatDrosophilaflies display a robust attraction / repulsion profile for a range of objects sizes in this paradigm, and that this visual preference profile remains evident under a variety of conditions and persists into old age. We also demonstrate a level of flexibility in this behavior: innate repulsion to certain objects could be transiently overridden if these were novel, although this effect was only evident in younger flies. Finally, we show that a reward circuit in the fly brain,Drosophilaneuropeptide F (dNPF), can be recruited to guide visual decision-making. Optogenetic activation of dNPF-expressing neurons converted a visually repulsive object into a more attractive object. This suggests that dNPF activity in theDrosophilabrain guides ongoing visual choices, to override innate preferences and thereby provide a necessary level of behavioral flexibility in visual decision-making.
A domestication history of dynamic adaptation and genomic deterioration in sorghum
Authors: Smith Oliver , Nicholson William V , Kistler Logan , Mace Emma , Clapham Alan , Rose Pamela , Stevens Chris , Ware Roselyn , Samavedam Siva , Barker Guy , Jordan David , Fuller Dorian Q , Allaby Robin G 
Published: June 2018

AbstractThe evolution of domesticated cereals was a complex interaction of shifting selection pressures and repeated introgressions. Genomes of archaeological crops have the potential to reveal these dynamics without being obscured by recent breeding or introgression. We report a temporal series of archaeogenomes of the crop sorghum (Sorghum bicolor) from a single locality in Egyptian Nubia. These data indicate no evidence for the effects of a domestication bottleneck but instead suggest a steady decline in genetic diversity over time coupled with an accumulating mutation load. Dynamic selection pressures acted sequentially on architectural and nutritional domestication traits, and adaptation to the local environment. Later introgression between sorghum races allowed exchange of adaptive traits and achieved mutual genomic rescue through an ameliorated mutation load. These results reveal a model of domestication in which genomic adaptation and deterioration was not focused on the initial stages of domestication but occurred throughout the history of cultivation.
Jag1 modulates an oscillatory Dll1-Notch-Hes1 signaling module to coordinate growth and fate of pancreatic progenitors
Authors: Seymour Philip A. , Collin Caitlin A. , Egeskov-Madsen Anuska l. R. , Jørgensen Mette C. , Shimojo Hiromi , Imayoshi Itaru , de Lichtenberg Kristian H. , Kopan Raphael , Kageyama Ryoichiro , Serup Palle 
Published: June 2018

SummaryNotch signaling controls proliferation of multipotent pancreatic progenitor cells (MPCs) and their segregation intobipotentprogenitors (BPs) and unipotentpro-acinar cells (PACs). Here we uncover fast ultradian oscillations in the ligand Dll1, and the transcriptional effector Hes1, which proved crucial for MPC expansion. Conversely Jag1, a uniformly expressed ligand, curbed MPC growth, but as expression later segregated to PACs it proved critical for specifying all but the most proximal 5% of BPs, while BPs were entirely lost inJag1,Dll1double mutants. Moreover, experimentally induced changes in Hes1 oscillation parameters was associated with selective adoption of BP or PAC fates. Anatomically, ductal morphogenesis and organ architecture is minimally perturbed inJag1mutants until later stages, when ductal remodeling fails and signs of acinar-to-ductal metaplasia appear. Our study uncovers oscillating Notch activity in the developing pancreas, which along with modulation by Jag1 is required to coordinate MPC growth and fate.