bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns of Opioid Use and Risk of Opioid Overdose Death Among Medicaid Patients
Authors: Garg Renu K. , Fulton-Kehoe Deborah , Franklin Gary M. 
Published: June 2017

Background:
The Centers for Disease Control and Prevention recognizes Medicaid as a high-risk population for fatal opioid overdose. Further research is needed to identify factors that put Medicaid patients at increased risk.

Objective:
To determine whether patterns of opioid use are associated with risk of opioid-related mortality among opioid users.

Design:
This is a retrospective cohort study.

Patients:
In total, 150,821 noncancer pain patients aged 18–64 years with ≥1 opioid prescription, April 2006 to December 2010, Washington Medicaid.

Measures:
Average daily dose (morphine equivalents), opioid schedule/duration of action, sedative-hypnotic use.

Results:
Compared with patients at 1–19 mg/d, risk of opioid overdose death significantly increased at 50–89 mg/d [adjusted hazard ratio (aHR), 2.3; 95% confidence interval (CI), 1.4–4.1], 90–119 mg/d (aHR, 4.0; 95% CI, 2.2–7.3), 120–199 mg/d (aHR, 3.8; 95% CI, 2.1–6.9), and ≥200 mg/d (aHR, 4.9; 95% CI, 2.9–8.1). Patients using long-acting plus short-acting Schedule II opioids had 4.7 times the risk of opioid overdose death than non-Schedule II opioids alone (aHR, 4.7; 95% CI, 3.3–6.9). Sedative-hypnotic use compared with nonuse was associated with 6.4 times the risk of opioid overdose death (aHR, 6.4; 95% CI, 5.0–8.4). Risk was particularly high for opioids combined with benzodiazepines and skeletal muscle relaxants (aHR, 12.6; 95% CI, 8.9–17.9). Even at opioid doses 1–19 mg/d, patients using sedative-hypnotics concurrently had 5.6 times the risk than patients without sedative-hypnotics (aHR, 5.6; 95% CI, 1.6–19.3).

Conclusions:
Our findings support Federal guideline-recommended dosing thresholds in opioid prescribing. Concurrent sedative-hypnotic use even at low opioid doses poses substantially greater risk of opioid overdose.
Effect of Stimulus Type and Motion on Smooth Pursuit in Adults and Children
Authors: Vinuela-Navarro Valldeflors , Erichsen Jonathan T. , Williams Cathy , Woodhouse J. Margaret 
Published: June 2017

ABSTRACT

Purpose
This study presents a two-degree customized animated stimulus developed to evaluate smooth pursuit in children and investigates the effect of its predetermined characteristics (stimulus type and size) in an adult population. Then, the animated stimulus is used to evaluate the impact of different pursuit motion paradigms in children.

Methods
To study the effect of animating a stimulus, eye movement recordings were obtained from 20 young adults while the customized animated stimulus and a standard dot stimulus were presented moving horizontally at a constant velocity. To study the effect of using a larger stimulus size, eye movement recordings were obtained from 10 young adults while presenting a standard dot stimulus of different size (1° and 2°) moving horizontally at a constant velocity. Finally, eye movement recordings were obtained from 12 children while the 2° customized animated stimulus was presented after three different smooth pursuit motion paradigms. Performance parameters, including gains and number of saccades, were calculated for each stimulus condition.

Results
The animated stimulus produced in young adults significantly higher velocity gain (mean: 0.93; 95% CI: 0.90–0.96; P = .014), position gain (0.93; 0.85–1; P = .025), proportion of smooth pursuit (0.94; 0.91–0.96, P = .002), and fewer saccades (5.30; 3.64–6.96, P = .008) than a standard dot (velocity gain: 0.87; 0.82–0.92; position gain: 0.82; 0.72–0.92; proportion smooth pursuit: 0.87; 0.83–0.90; number of saccades: 7.75; 5.30–10.46). In contrast, changing the size of a standard dot stimulus from 1° to 2° did not have an effect on smooth pursuit in young adults (P > .05). Finally, smooth pursuit performance did not significantly differ in children for the different motion paradigms when using the animated stimulus (P > .05).

Conclusions
Attention-grabbing and more dynamic stimuli, such as the developed animated stimulus, might potentially be useful for eye movement research. Finally, with such stimuli, children perform equally well irrespective of the motion paradigm used.
Immediate Breast Reconstruction with Abdominal Free Flap and Adjuvant Radiotherapy: Evaluation of Quality of Life and Outcomes
Authors: Pont Luis Parra , Marcelli Stefano , Robustillo Manuel , Song Dajiang , Grandes Daniel , Martin Marcos , Iglesias Israel , Aso Jorge , Laloumet Iñaki , Díaz Antonio J. 
Published: June 2017

Background:
The effects of postoperative radiotherapy on free flap–based breast reconstruction are still controversial. Poor outcomes, breast distortion, and fat necrosis have been traditionally documented. The aim of this study was to evaluate whether adjuvant radiotherapy affects the quality of life, satisfaction, and cosmetic result in patients undergoing immediate breast reconstruction with autologous free flap.

Methods:
Between January of 2013 and December of 2016, 230 patients underwent mastectomy with immediate free flap reconstruction at the authors’ institution. Patients were divided into two groups depending on whether they received postmastectomy radiotherapy. Quality of life measured with the BREAST-Q questionnaire, self-reported aesthetic outcomes, and general satisfaction were assessed and compared. Fat necrosis of the flap and its severity were also analyzed as the main surgical outcomes.

Results:
Mean follow-up time after reconstruction was 23 months (range, 6 to 48 months). No significant difference in quality of life or satisfaction scores were found between patients that underwent postmastectomy radiotherapy and patients who did not receive adjuvant radiotherapy. There were no significant differences in rates of fat necrosis between the groups (11.1 percent versus 13.76 percent; p = 0.75).

Conclusions:
Postmastectomy radiotherapy in patients undergoing immediate breast reconstruction with free flaps does not seem to affect quality of life, satisfaction with the outcome, or the cosmetic result as perceived by the patients. The potential need for postoperative radiotherapy should not hinder women from the benefits of autologous immediate breast reconstruction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, III.
Novel Approach for Maximizing Follow-Up in Cosmetic Surgery Clinical Trials: The Ideal Implant Core Trial Experience
Authors: Mueller Melissa A. , Nichter Larry S. , Hamas Robert S. 
Published: June 2017

Background:
High follow-up rates are critical for robust research with minimal bias, and are particularly important for breast implant Core Studies seeking U.S. Food and Drug Administration approval. The Core Study for IDEAL IMPLANT, the most recently U.S. Food and Drug Administration–approved breast implant, used a novel incentive payment model to achieve higher follow-up rates than in previous breast implant trials.

Methods:
At enrollment, $3500 was deposited into an independent, irrevocable trust for each of the 502 subjects and invested in a diversified portfolio. If a follow-up visit is missed, the subject is exited from the study and compensated for completed visits, but the remainder of her share of the funds stay in the trust. At the conclusion of the 10-year study, the trust will be divided among those subjects who completed all required follow-up visits. For primary and revision augmentation cohorts, the U.S. Food and Drug Administration published follow-up rates from Core Studies were compared for all currently available breast implants.

Results:
Five-year follow-up rates for the IDEAL IMPLANT Core Study are higher for both primary augmentation and revision augmentation cohorts (94.9 percent and 96.7 percent, respectively) when compared to all other trials that have used U.S. Food and Drug Administration standardized follow-up reporting (MemoryShape, Allergan 410, and Sientra Core Studies).

Conclusions:
This trial demonstrates the utility of a novel incentive strategy to maximize follow-up in cosmetic surgery patients. This strategy may benefit future cosmetic surgery trials and perhaps any prospective research trial by providing more complete data.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, IV.
The challenges of hydrogen and metals
Authors: Paxton A. T. , Sutton A. P. , Finnis M. W. 
Published: June 2017

The Royal Society Scientific Discussion Meeting ‘The challenges of hydrogen and metals’ was held in Carlton House Terrace, London, UK, on 16–18 January 2017. This is the introductory article to the discussion meeting issue which includes contributed papers and seven discussion papers. Here, we introduce the motivation to hold the Meeting and give a brief overview of the contents. We conclude with acknowledgements.
This article is part of the themed issue ‘The challenges of hydrogen and metals’.
An anti-cancer binary system activated by bacteriophage HK022 Integrase
Authors: Elias Amer , Spector Itay , Gritsenko Natasha , Zilberstein Yael , Gorovits Rena , Prag Gali , Kolot Mikhail 
Published: June 2017

ABSTRACTCancer gene therapy is a great promising tool for cancer therapeutics due to the specific targeting based on the cancerous gene expression background. Binary systems based on site-specific recombination are one of the most effective potential approaches for cancer gene therapy. In these systems, a cancer specific promoter expresses a site-specific recombinase/integrase that in turn controls the expression of a toxin gene. In the current study, we have developed a new HK022 bacteriophage Integrase (Int) based binary system activating a Diphtheria toxin (DTA) gene expression specifically in cancer cells. We have demonstrated the efficiency, and the high specificity of the systemin vitroin cell cultures andin vivoin a lung cancer mouse model. Strikingly, different apoptotic and anti-apoptotic factors demonstrated a remarkable efficacy killing capability of the Int-based binary system compared to the conventionalhTERT-DTAmono system in the LLC-Kat lung cancer mice model; we observed that the activehTERTpromoter down regulation by the transcription factors Mad-1 is the cornerstone of this phenomenon. The new Int-based binary system offers advantages over already known counterparts and may therefore be developed into a safer and efficient cancer treatment technology.
Genetic mapping of species differences via “in vitrocrosses” in mouse embryonic stem cells
Authors: Lazzarano Stefano , Kučka Marek , Castro João P. L. , Naumann Ronald , Medina Paloma , Fletcher Michael N. C. , Wombacher Rebecka , Gribnau Joost , Hochepied Tino , Libert Claude , Chan Yingguang Frank 
Published: June 2017

AbstractDiscovering the genetic changes underlying species differences is a central goal in evolutionary genetics. However, hybrid crosses between species in mammals often suffer from hybrid sterility, greatly complicating genetic dissection of trait variation. Here we describe a simple, robust and transgene-free technique to make “in vitrocrosses” in hybrid mouse embryonic stem cells by inducing random mitotic crossovers with the drug ML216, which inhibitsBloom syndrome(BLM). Starting with an interspecific hybrid (betweenMus musculusandMus spretus) embryonic stem cell line spanning 1.5 million years of divergence, we demonstrate the feasibility of mapping enzymatic differences across species within weeks and the possibility of re-deriving whole mice. Our work shows howin vitrocrosses can overcome major bottlenecks like hybrid sterility in traditional mouse breeding to address fundamental questions in evolutionary biology.Impact StatementBy mixing hybrid mouse genomes in stem cells via mitotic recombination, genetic mapping and hybrid mosaic mice can be achieved in weeks, even across species barriers.
Strain-Specific Human Natural Killer Cell Recognition of Influenza A Virus
Authors: Kronstad Lisa M. , Seiler Christof , Vergara Rosemary , Holmes Susan P. , Blish Catherine A. 
Published: June 2017

AbstractInnate Natural killer (NK) cells employ an array of surface receptors to detect ‘altered self’ induced by infection or malignancy. Despite their decisive role in early antiviral immunity, the cellular mechanisms governing if or how they discriminate between viral infections remain unresolved. Here, we demonstrate that while human NK cells are capable of reducing infection levels of distinct influenza A strains, the A/California/07/2009 (pH1N1) strain induces a significantly more robust IFN-γ response than A/Victoria/361/2011 (H3N2) and all other strains tested. This surprising degree of strain specificity results in part from the inability of the pH1N1 strain to downregulate the activating ligands CD112 (Nectin-2) and CD54 (ICAM-1) as efficiently as the H3N2 strain, leading to enhanced NK cell detection and IFN-γ secretion. A network analysis of differentially expressed transcripts identifies the interferon α/β receptor (IFNAR) pathway as an additional, critical determinant of this strain-specific response. Strain-specific downregulation of NK cell activating ligands and modulation of type I IFN production represents a previously unrecognized influenza immunoevasion tactic and could present new opportunities to modulate the quality and quantity of the innate antiviral response for therapeutic benefit.One Sentence SummaryHuman natural killer cells distinguish between Influenza A strains using a combinatorial cytokine priming and receptor-ligand signaling mechanism.
PhenoSpD: an integrated toolkit for phenotypic correlation estimation and multiple testing correction using GWAS summary statistics
Authors: Zheng Jie , Richardson Tom G. , Millard Louise A. C. , Hemani Gibran , Raistrick Christopher , Vilhjalmsson Bjarni , Haycock Philip , Gaunt Tom R 
Published: June 2017

AbstractBackgroundIdentifying phenotypic correlations between complex traits and diseases can provide useful etiological insights. Restricted access to individual-level phenotype data makes it difficult to estimate large-scale phenotypic correlation across the human phenome. State-of-the-art methods, metaCCA and LD score regression, provide an alternative approach to estimate phenotypic correlation using genome-wide association study (GWAS) summary statistics.ResultsHere, we present an integrated R toolkit, PhenoSpD, to 1) apply metaCCA (or LD score regression) to estimate phenotypic correlations using GWAS summary statistics; and 2) to utilize the estimated phenotypic correlations to inform correction of multiple testing for complex human traits using the spectral decomposition of matrices (SpD). The simulations suggest it is possible to estimate phenotypic correlation using samples with only a partial overlap, but as overlap decreases correlations will attenuate towards zero and multiple testing correction will be more stringent than in perfectly overlapping samples. In a case study, PhenoSpD using GWAS results suggested 324.4 independent tests among 452 metabolites, which is close to the 296 independent tests estimated using true phenotypic correlation. We further applied PhenoSpD to estimated 7,503 pair-wise phenotypic correlations among 123 metabolites using GWAS summary statistics from Kettunen et al. and PhenoSpD suggested 44.9 number of independent tests for theses metabolites.ConclusionPhenoSpD integrates existing methods and provides a simple and conservative way to reduce dimensionality for complex human traits using GWAS summary statistics, which is particularly valuable for post-GWAS analysis of complex molecular traits.AvailabilityR code and documentation for PhenoSpD V1.0.0 is available online (https://github.com/MRCIEU/PhenoSpD).
Genetics and epigenetic alterations of hexaploid early generation derived from hybrid betweenBrassica napusandB. oleracea
Authors: Li Qinfei , Xiong Zhiyong , Mei Jiaqin , Song Hongyuan , Qian Wei 
Published: June 2017

AbstractGood fertility was observed previously in hexaploid derived from hybrid (ACC) between calona ‘Zhongshuang 9’(Brassica napus, 2n = 38, AACC) and kale ‘SWU01’ (B. oleracea var. acephala, 2n = 18, CC). However, the mechanism to underlying the character is unknown. In the present study, genetic and epigenetic alterations of S0, 6 S1, and 18 of their S2 progenies with hexaploid chromosome conformation (20A + 36C) were selected to compare with ACC and their parental species. 13.08% and 26.45% polymorphism alleles different from two parental species were identified in ACC via 58 SSR (simple sequence repeats) and 14 MSAP (methylation sensitive amplified polymorphism), respectively. 33.74% new alleles in DNA methylation, but not in DNA sequence were detected in S0 after chromosome doubling of ACC. DNA profilling revealed a little genetic but much epigenetic differences among S0, S1 and S2 generations. Genetic alteration was relatively stable, because only 8.09% and 3.21% alleles inheriated from ACC were changed in S2 and S1, respectively. While on average of 52.44 ± 5.32% DNA methylation site inherited from ACC were detected in S1, and 41.52 ± 9.04% in S2 due to dramatic epigenetic variance among early generations. New DNA methylation sites occurred in S0 would inheritated into the successive generations, but the frequency was decreased because some new site might be recovered. It demonstrated that much DNA methylation but a little DNA sequence variance was occurred in hexaploid early generation.
Spatial resource heterogeneity increases diversity and evolutionary potential
Authors: Dolson Emily L. , Pérez Samuel G. , Olson Randal S. , Ofria Charles 
Published: June 2017

AbstractSpatial heterogeneity is believed to be an evolutionary driver of biodiversity. Variability in the distribution of resource patches can allow an environment to support a wider variety of phenotypes for selection to act upon at the ecosystem level, which may lead to more species. However, the generality of this principle has not been thoroughly tested, as the relevant adaptive dynamics occur on evolutionary timescales. We overcame this challenge by performing experiments on populations of digital organisms in the Avida Digital Evolution Platform, in which we investigated the impact of spatial resource heterogeneity on phenotypic diversity. Since an important benefit of diversity may be increased evolutionary potential, we also tracked the probability of a complex trait evolving in the context of various levels of spatial heterogeneity. We found that spatial entropy and phenotypic diversity have a strong positive correlation and this relationship is consistent across various spatial configurations. Diversity also increases evolutionary potential, but has a much smaller impact than other components of environmental composition. The most important of these components was the mean number of resources present in locations across the environment, likely owing to the importance of building blocks for the evolution of complex features. These results suggest that a general relationship exists between spatial heterogeneity and diversity, beyond the specific ecosystems and timescales in which it has previously been studied. By examining this relationship in the context of phenotypic evolution, we advance a mechanistic understanding of the resulting dynamics. Moreover, our results suggest that the likelihood of evolving various traits can be impacted by the spatial configuration of patches in which these traits are advantageous. These findings have implications for both evolutionary biology and evolutionary computation, as generating and maintaining diversity is critical to all forms of evolution.
The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito
Authors: Hammond Andrew , Kyrou Kyros , Bruttini Marco , North Ace , Galizi Roberto , Karlsson Xenia , Carpi Francesco M , D’Aurizio Romina , Crisanti Andrea , Nolan Tony 
Published: June 2017

ABSTRACTGene drives have enormous potential for the control of insect populations of medical and agricultural relevance. By preferentially biasing their own inheritance gene drives can rapidly introduce genetic traits even if these confer a negative fitness on the population.We have recently developed gene drives based on a CRISPR nuclease construct that is designed to disrupt key genes essential for female fertility in the malaria mosquito. The construct copies itself and the associated genetic disruption from one homologous chromosome to another during gamete formation, in a process called homing that ensures the majority of offspring inherit the drive. Such drives have the potential to cause long-lasting, sustainable population suppression though they are also expected to impose a large selection pressure for resistance in the mosquito. One of these population suppression gene drives showed rapid invasion of a caged population over 4 generations, establishing proof of principle for this technology. In order to assess the potential for the emergence of resistance to the gene drive in this population we allowed it to run for 25 generations and monitored the frequency of the gene drive over time. Following the initial increase of the gene drive we noticed a gradual decrease in its frequency that was accompanied emergence of small, nuclease-induced mutations at the target gene that are resistant to further cleavage and restore its functionality. Such mutations show rates of increase consistent with positive selection in the face of the gene drive. Our findings represent the first documented example of selection for resistance to a synthetic gene drive and lead to important design recommendations and considerations in order to mitigate for resistance for future gene drive applications.
A Growing Microcolony can Survive and Support Persistent Propagation of Virulent Phages
Authors: Eriksen Rasmus Skytte , Svenningsen Sine Lo , Sneppen Kim , Mitarai Namiko 
Published: June 2017

Bacteria form colonies and secrete extracellular polymeric substances that surround the individual cells. These spatial structures are often associated with collaboration and quorum sensing between the bacteria. Here we investigate the mutual protection provided by spherical growth of a monoclonal colony during exposure to phages that proliferate on its surface. As a proof of concept we exposed growing colonies ofEscherichia colito a virulent mutant of phage P1. When the colony consists of less than ~ 50000 members it is eliminated, while larger initial colonies allow long-term survival because the growth of bacteria throughout the spherical colony exceeds the killing of bacteria on the surface. A mathematical model pinpoints how this critical colony size depends on key parameters in the phage infection cycle. Surprisingly, we predict that a higher phage adsorption rate would allow substantially smaller colonies to survive a virulent phage.Significance StatementBacteria are repeatedly exposed to an excess of phages, and carry evidence of this in terms of multiple defense mechanisms encoded in their genome. In addition to molecular mechanisms, bacteria may exploit the defense of spatial refuges. Here we demonstrate how bacteria can limit the impact of a virulent phage attack by growing as a colony which only exposes its surface to phages. We identify a critical size of the initial colony, below which the phages entirely eliminates the colony, and above which the colony continues to grow despite the presence of phages. Our study suggests that coexistence of phages and bacteria is strongly influenced by the spatial composition of microcolonies of susceptible bacteria.