bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure‐response analysis after subcutaneous administration of RBP‐7000, a once‐a‐month long‐acting Atrigel formulation of risperidone
Authors: Ivaturi Vijay , Gopalakrishnan Mathangi , Gobburu Jogarao V. S. , Zhang Weiyan , Liu Yongzhen , Heidbreder Christian , Laffont Celine M. 
Published: January 2017

AimsA new, long‐acting, subcutaneous (SC) formulation of risperidone (RBP‐7000) has been developed for the treatment of schizophrenia to address issues of non‐adherence associated with oral risperidone treatment. The objective of this work was to establish an exposure‐response relationship between total active moiety (AM) plasma exposure (risperidone + 9‐hydroxy‐risperidone) and Positive and Negative Syndrome Scale (PANSS) or Clinical Global Impression severity (CGI‐S) scores using data from a registration trial.MethodsThis was a Phase 3 randomized, double‐blind, placebo‐controlled, multicenter study in 354 patients to evaluate the efficacy, safety and tolerability of RBP‐7000 (90 mg and 120 mg). Non‐linear mixed effects modelling was used to develop an integrated population pharmacokinetic/pharmacodynamic (PK/PD) model that included a joint PK model for risperidone and 9‐hydroxy‐risperidone with placebo and drug‐effect models to establish the relation between total AM exposure and PANSS or CGI‐S scores.ResultsCYP2D6 poor and intermediate metabolizers had lower formation rates of 9‐hydroxy‐risperidone (94% and 76% lower, respectively) compared to the extensive CYP2D6 metabolizers. The maximum placebo‐corrected relative decrease in PANSS score from baseline following RBP‐7000 treatment was 5.4%, half of which could be achieved at plasma concentrations of 4.6 ng ml−1 of the total AM. A proportional odds model for the CGI‐S score related the total AM plasma concentration to the probability of improving/worsening scores over time.ConclusionsExposure‐response analysis was established between total AM concentrations and PANSS and CGI‐S scores, with good precision in parameter estimates. CYP2D6 phenotype on risperidone metabolism was the only identified covariate.
A Penalized Framework for Distributed Lag Non-Linear Models
Authors: Gasparrini Antonio , Scheipl Fabian , Armstrong Ben , Kenward Michael G. 
Published: January 2017

Summary
Distributed lag non-linear models (DLNMs) are a modelling tool for describing potentially non-linear and delayed dependencies. Here, we illustrate an extension of the DLNM framework through the use of penalized splines within generalized additive models (GAM). This extension offers built-in model selection procedures and the possibility of accommodating assumptions on the shape of the lag structure through specific penalties. In addition, this framework includes, as special cases, simpler models previously proposed for linear relationships (DLMs). Alternative versions of penalized DLNMs are compared with each other and with the standard unpenalized version in a simulation study. Results show that this penalized extension to the DLNM class provides greater flexibility and improved inferential properties. The framework exploits recent theoretical developments of GAMs and is implemented using efficient routines within freely available software. Real-data applications are illustrated through two reproducible examples in time series and survival analysis.
Synthesis and characterization of a novel series of 1,4‐dihydropyridine analogues for larvicidal activity against Anopheles arabiensis
Authors: Dharma Rao Bhaskara D. , Bhandary Subhrajyoti , Chopra Deepak , Venugopala Katharigatta N. , Gleiser Raquel M. , Kasumbwe Kabange , Odhav Bharti 
Published: January 2017

The new‐fangled bis(4‐substituted benzyl) 4‐(4‐substitued phenyl)‐2,6‐dimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate derivatives were synthesized by the union of substituted aryl aldehyde, tert‐butyl acetoacetate, ammonium carbonate with 4‐substituted benzyl alcohol via Hantzsch ester synthesis in aqueous medium under catalyst‐free conditions. The newly synthesized compounds were characterized by spectroscopic techniques such as IR, NMR (1H and 13C), ESI mass, elemental analysis, and single‐crystal X‐ray diffraction. The characterized title compounds were evaluated for the larvicidal activity against Anopheles arabiensis by standard WHO larvicidal assay method using Temephos as standard at 4 μg/ml. The title compounds bis(4‐methoxybenzyl) 2,6‐dimethyl‐4‐(4‐nitrophenyl)‐1,4‐dihydropyridine‐3,5‐dicarboxylate and bis(4‐chlorobenzyl) 2,6‐dimethyl‐4‐(4‐nitrophenyl)‐1,4‐dihydropyridine‐3,5‐dicarboxylate exhibited promising larvicidal activity at 65.6% and 72.2%, respectively, when compared with the standard compound at 98.9%.
siRNA‐loaded liposomes: Inhibition of encystment of Acanthamoeba and toxicity on the eye surface
Authors: Faber Kathrin , Zorzi Giovanni K. , Brazil Nathalya T. , Rott Marilise B. , Teixeira Helder F. 
Published: January 2017

Current treatments for Acanthamoeba keratitis are unspecific. Because of the presence of the resilient cyst form of the parasite, the infection is persistent. Silencing the key protein of cyst formation, glycogen phosphorylase, has shown potential for reducing encystment processes of the Acanthamoeba trophozoite. However, a suitable carrier to protect and deliver siRNA sequences is still needed. DOTAP:DOPE:DSPE‐PEG liposomes were prepared by three different techniques and used to associate a therapeutic siRNA sequence. Liposomes prepared by film hydration followed by membrane extrusion were considered the most adequate ones with average size of 250 nm and zeta potential of +45 mV, being able to associate siRNA for at least 24 hr in culture medium. siRNA‐liposomes could inhibit up to 66% of the encystment process. Cell viability studies demonstrated MTT reduction capacity higher than 80% after 3 hr incubation with this formulation. After 24 hr of incubation, LDH activity ranged for both the formulations from around 4% to 40%. In vivo tolerance studies in mice showed no macroscopic alteration in the eye structures up to 24 hr after eight administrations during 1 day. Histological studies showed regular tissue architecture without any morphological alteration. Overall, these results suggest that the formulations developed are a promising new strategy for the treatment of ocular keratitis caused by Acanthamoeba spp.
Evaluating living donor kidney transplant rates: Are you reaching your potential?
Authors: Matar Abraham J. , Files John , Burkholder Ryan , Chin Thomas , Angelis Michael 
Published: January 2017

AbstractBackgroundTraditionally, living donor kidney transplant (LDKT) rate has been calculated as a percentage of total kidney transplant volume. We believe this calculation to be inherently flawed because the number of deceased donor kidney transplants has no bearing on the number of LDKT performed. We propose an alternative calculation of LDKT rate as a percentage of the number of new waitlist registrants.MethodsWe evaluated 192 adult transplant centers in the United States with respect to their LDKT rate according to both the traditional and proposed calculations, using data from the scientific registry of transplant recipients between July 2014 and June 2015.ResultsThe median LDKT rate for every 100 new waitlist registrants was 12.3, compared to 27.9 for every 100 total kidney transplants. Based on our proposed calculation of LDKT rate, 16.7% of transplant centers were misevaluated when compared to the national mean using the traditional method.ConclusionsA new calculation of LDKT rate based on new waitlist registrants, and not total kidney transplants, is necessary to eliminate the bias associated with the traditional method, allowing for the identification of centers for improvement as well as each individual center's true potential based on their patient demographics.
Multidrug‐resistant organisms in allogeneic hematopoietic cell transplantation
Authors: Heidenreich Daniela , Kreil Sebastian , Nolte Florian , Hofmann Wolf K. , Miethke Thomas , Klein Stefan A. 
Published: January 2017

AbstractObjectiveMultidrug‐resistant organisms (MDRO) are a challenge in allogeneic hematopoietic cell transplantation (HCT). However, in the literature there is no comprehensive analysis on MDRO in HCT. In this retrospective, single‐center analysis, we appraised prevalence and clinical impact of MDRO in 98 consecutive allogeneic HCT patients.MethodPrior to the conditioning (baseline) and whenever clinically indicated patients underwent a full screening for MDRO (stool and urine cultures, swabs from several body regions).ResultsIt turned out that 26 patients were colonized by 33 MDRO, either at baseline (n=16) or at any other time until day 100 post‐transplantation. Of these 26 patients, eight developed an infection with MDRO, four of them by 4MRGN Pseudomonas aeruginosa, and three of them died MDRO‐related. However, there was no significant difference between MDRO‐colonized and non‐colonized patients regarding overall survival (OS) and non‐relapse‐mortality (NRM). There was only a trend toward a higher NRM in patients already colonized by MDRO at baseline. This was due to the high NRM in multidrug‐resistant P. aeruginosa‐colonized patients.ConclusionIn summary, colonization with MDRO other than P. aeruginosa had no negative impact on NRM and OS. Patients colonized by multidrug‐resistant P. aeruginosa had a dismal outcome. HCT of these patients should be considered with care. Screening for MDRO in the pretransplant work‐up is suggested.
Responses to atmospheric CO2 concentrations in crop simulation models: a review of current simple and semicomplex representations and options for model development
Authors: Vanuytrecht Eline , Thorburn Peter J. 
Published: January 2017

AbstractElevated atmospheric CO2 concentrations ([CO2]) cause direct changes in crop physiological processes (e.g. photosynthesis and stomatal conductance). To represent these CO2 responses, commonly used crop simulation models have been amended, using simple and semicomplex representations of the processes involved. Yet, there is no standard approach to and often poor documentation of these developments. This study used a bottom‐up approach (starting with the APSIM framework as case study) to evaluate modelled responses in a consortium of commonly used crop models and illuminate whether variation in responses reflects true uncertainty in our understanding compared to arbitrary choices of model developers. Diversity in simulated CO2 responses and limited validation were common among models, both within the APSIM framework and more generally. Whereas production responses show some consistency up to moderately high [CO2] (around 700 ppm), transpiration and stomatal responses vary more widely in nature and magnitude (e.g. a decrease in stomatal conductance varying between 35% and 90% among models was found for [CO2] doubling to 700 ppm). Most notably, nitrogen responses were found to be included in few crop models despite being commonly observed and critical for the simulation of photosynthetic acclimation, crop nutritional quality and carbon allocation. We suggest harmonization and consideration of more mechanistic concepts in particular subroutines, for example, for the simulation of N dynamics, as a way to improve our predictive understanding of CO2 responses and capture secondary processes. Intercomparison studies could assist in this aim, provided that they go beyond simple output comparison and explicitly identify the representations and assumptions that are causal for intermodel differences. Additionally, validation and proper documentation of the representation of CO2 responses within models should be prioritized.
Annual balances and extended seasonal modelling of carbon fluxes from a temperate fen cropped to festulolium and tall fescue under two‐cut and three‐cut harvesting regimes
Authors: Kandel Tanka P. , Elsgaard Lars , Lærke Poul E. 
Published: January 2017

AbstractThis study reports the annual carbon balance of a drained riparian fen under two‐cut or three‐cut managements of festulolium and tall fescue. CO2 fluxes measured with closed chambers were partitioned into gross primary production (GPP) and ecosystem respiration (ER) for modelling according to environmental factors (light and temperature) and canopy reflectance (ratio vegetation index, RVI). Methodological assessments were made of (i) GPP models with or without temperature functions (Ft) to adjust GPP constraints imposed by low temperature (<10 °C) and (ii) ER models with RVI or GPP parameters as biomass proxies. The sensitivity of the models was also tested on partial datasets including only alternate measurement campaigns and on datasets only from the crop growing period. Use of Ft in GPP models effectively corrected GPP overestimation in cold periods, and this approach was used throughout. Annual fluxes obtained with ER models including RVI or GPP parameters were similar, and also annual GPP and ER fluxes obtained with full and partial datasets were similar. Annual CO2 fluxes and biomass yield were not significantly different in the crop/management combinations although the individual collars (n = 12) showed some variations in GPP (−1818 to −2409 g CO2‐C m−2), ER (1071 to 1738 g CO2‐C m−2), net ecosystem exchange (NEE, −669 to −949 g CO2‐C m−2) and biomass yield (556 to 1044 g CO2‐C m−2). Net ecosystem carbon balance (NECB), as the sum of NEE and biomass carbon export, was only slightly negative to positive in all crop/management combinations. NECBs, interpreted as emission factors, tended to favour the least biomass producing systems as the best management options in relation to climate saving carbon balances. Yet, considering the down‐stream advantages of biomass for fossil fuel replacement, yield‐scaled carbon fluxes are suggested to be given additional considerations for comparison of management options in terms of atmospheric impact.
Cover crop root contributions to soil carbon in a no‐till corn bioenergy cropping system
Authors: Austin Emily E. , Wickings Kyle , McDaniel Marshall D. , Robertson G. Philip , Grandy A. Stuart 
Published: January 2017

AbstractCrop residues are potential biofuel feedstocks, but residue removal may reduce soil carbon (C). The inclusion of a cover crop in a corn bioenergy system could provide additional biomass, mitigating the negative effects of residue removal by adding to stable soil C pools. In a no‐till continuous corn bioenergy system in the northern US Corn Belt, we used 13CO2 pulse labeling to trace plant C from a winter rye (Secale cereale) cover crop into different soil C pools for 2 years following rye cover crop termination. Corn stover left as residue (30% of total stover) contributed 66, corn roots 57, rye shoots 61, rye roots 50, and rye rhizodeposits 25 g C m−2 to soil. Five months following cover crop termination, belowground cover crop inputs were three times more likely to remain in soil C pools than were aboveground inputs, and much of the root‐derived C was in mineral‐associated soil fractions. After 2 years, both above‐ and belowground inputs had declined substantially, indicating that the majority of both root and shoot inputs are eventually mineralized. Our results underscore the importance of cover crop roots vs. shoots and the importance of cover crop rhizodeposition (33% of total belowground cover crop C inputs) as a source of soil C. However, the eventual loss of most cover crop C from these soils indicates that cover crops will likely need to be included every year in rotations to accumulate soil C.
Studies on drinking water intake of fallow deer, sheep and mouflon under semi‐natural pasture conditions
Authors: Fischer Andreas , Kaiser Thomas , Pickert Jürgen , Behrendt Axel 
Published: January 2017

AbstractThe aim of the investigation was to determine the water requirements of adult fallow deer (Dama dama), Skudde sheep (Ovis ammon) and mouflon (Ovis orientalis musimon) kept under the same conditions. This study was intended to allow the development of basic principles and recommendations for improving drinking water management in the production of fallow deer, sheep, and mouflon, taking into account the different reproductive statuses of these three species. At a fen, the water intake of the animals was recorded for three consecutive years (2011–2013) during the grazing period (1 May–31 October). The results were based on the regular measurement of the animals’ water intake under pasture management. Three herd repetitions were carried out per species during early and late summer and autumn. Each test group consisted of 10 adult female animals. To enable a comparison of the drinking water consumption among species of different weights, the water intake of each animal was converted into the water intake per kg of metabolic live weight (W0.75). During the early summer fallow deer and sheep consumed a similar amount of water. The mouflon had relatively low water consumption; in the late summer and autumn (September and October), these animals drank only sporadically. All three species consumed more water in the first 3 months of the grazing period than in the last 3 months. Daily water consumption by sheep and deer increased with heat stress caused by higher temperatures and relative humidity, whereas mouflon were relatively immune to such environmental influences. It is recommended that the small ruminant species investigated should be offered a constant supply of drinking water when under pasture management.
The HIV‐1 envelope glycoprotein structure: nailing down a moving target
Authors: Ward Andrew B , Wilson Ian A 
Published: January 2017

SummaryStructure determination of the HIV‐1 envelope glycoprotein (Env) presented a number of challenges, but several high‐resolution structures have now become available. In 2013, cryo‐EM and x‐ray structures of soluble, cleaved SOSIP Env trimers from the clade A BG505 strain provided the first glimpses into the Env trimer fold as well as more the variable regions. A recent cryo‐EM structure of a native full‐length trimer without any stabilizing mutations had the same core structure, but revealed new insights and features. A more comprehensive and higher resolution understanding of the glycan shield has also emerged, enabling a more complete representation of the Env glycoprotein structure. Complexes of Env trimers with broadly neutralizing antibodies have surprisingly illustrated that most of the Env surface can be targeted in natural infection and that the neutralizing epitopes are almost all composed of both peptide and glycan components. These structures have also provided further evidence of the inherent plasticity of Env and how antibodies can exploit this flexibility by perturbing or even stabilizing the trimer to facilitate neutralization. These breakthroughs have stimulated further design and stabilization of Env trimers as well as other platforms to generate trimers that now span multiple subtypes. These Env trimers when used as immunogens, have led to the first vaccine‐induced neutralizing antibodies for structural and functional analyses.
Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development
Authors: Bonsignori Mattia , Liao Hua‐Xin , Gao Feng , Williams Wilton B. , Alam S. Munir , Montefiori David C. , Haynes Barton F. 
Published: January 2017

SummaryInduction of HIV‐1 broadly neutralizing antibodies (bnAbs) to date has only been observed in the setting of HIV‐1 infection, and then only years after HIV transmission. Thus, the concept has emerged that one path to induction of bnAbs is to define the viral and immunologic events that occur during HIV‐1 infection, and then to mimic those events with a vaccine formulation. This concept has led to efforts to map both virus and antibody events that occur from the time of HIV‐1 transmission to development of bnAbs. This work has revealed that a virus‐antibody “arms race” occurs in which a HIV‐1 transmitted/founder (TF) Env induces autologous neutralizing antibodies that can not only neutralize the TF virus but also can select virus escape mutants that in turn select affinity‐matured neutralizing antibodies. From these studies has come a picture of bnAb development that has led to new insights in host–pathogen interactions and, as well, led to insight into immunologic mechanisms of control of bnAb development. Here, we review the progress to date in elucidating bnAb B cell lineages in HIV‐1 infection, discuss new research leading to understanding the immunologic mechanisms of bnAb induction, and address issues relevant to the use of this information for the design of new HIV‐1 sequential envelope vaccine candidates.
Complex immune correlates of protection in HIV‐1 vaccine efficacy trials
Authors: Tomaras Georgia D. , Plotkin Stanley A. 
Published: January 2017

SummaryDevelopment of an efficacious HIV‐1 vaccine is a major priority for improving human health worldwide. Vaccine‐mediated protection against human pathogens can be achieved through elicitation of protective innate, humoral, and cellular responses. Identification of specific immune responses responsible for pathogen protection enables vaccine development and provides insights into host defenses against pathogens and the immunological mechanisms that most effectively fight infection. Defining immunological correlates of transmission risk in preclinical and clinical HIV‐1 vaccine trials has moved the HIV‐1 vaccine development field forward and directed new candidate vaccine development. Immune correlate studies are providing novel hypotheses about immunological mechanisms that may be responsible for preventing HIV‐1 acquisition. Recent results from HIV‐1 immune correlates work has demonstrated that there are multiple types of immune responses that together, comprise an immune correlate—thus implicating polyfunctional immune control of HIV‐1 transmission. An in depth understanding of these complex immunological mechanisms of protection against HIV‐1 will accelerate the development of an efficacious HIV‐1 vaccine.
Evolution of B cell analysis and Env trimer redesign
Authors: Karlsson Hedestam Gunilla B. , Guenaga Javier , Corcoran Martin , Wyatt Richard T. 
Published: January 2017

SummaryHIV‐1 and its surface envelope glycoproteins (Env), gp120 and gp41, have evolved immune evasion strategies that render the elicitation of effective antibody responses to the functional Env entry unit extremely difficult. HIV‐1 establishes chronic infection and stimulates vigorous immune responses in the human host; forcing selection of viral variants that escape cellular and antibody (Ab)‐mediated immune pressure, yet possess contemporary fitness. Successful survival of fit variants through the gauntlet of the human immune system make this virus and these glycoproteins a formidable challenge to target by vaccination, requiring a systematic approach to Env mimetic immunogen design and evaluation of elicited responses. Here, we review key aspects of HIV‐1 Env immunogenicity and immunogen re‐design, based on experimental data generated by us and others over the past decade or more. We further provide rationale and details regarding the use of newly evolving tools to analyze B cell responses, including approaches to use next generation sequencing for antibody lineage tracing and B cell fate mapping. Together, these developments offer opportunities to address long‐standing questions about the establishment of effective B cell immunity elicited by vaccination, not just against HIV‐1.