bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient-centered Outcomes in Participants of a Buprenorphine Monthly Depot (BUP-XR) Double-blind, Placebo-controlled, Multicenter, Phase 3 Study
Authors: Ling Walter , Nadipelli Vijay R. , Solem Caitlyn T. , Ronquest Naoko A. , Yeh Yu-Chen , Learned Susan M. , Mehra Vishaal , Heidbreder Christian 
Published: March 2019

Objective:
Opioid use disorder (OUD) is associated with physical, social, psychological, and economic burden. This analysis assessed the effects of RBP-6000, referred to as BUP-XR (extended-release buprenorphine), a subcutaneously injected, monthly buprenorphine treatment for OUD compared with placebo on patient-centered outcomes measuring meaningful life changes.

Methods:
Patient-centered outcomes were collected in a 24-week, phase 3, placebo-controlled study assessing the efficacy, safety, and tolerability of BUP-XR 300/300 mg (6 × 300 mg) and 300/100 mg (2 × 300 mg followed by 4 × 100 mg) injections in treatment-seeking participants with moderate-to-severe OUD. Measures included the EQ-5D-5L, SF-36v2, Medication Satisfaction Questionnaire, employment/insurance status, and healthcare resource utilization (HCRU). Changes from baseline to end of study were compared across treatment arms, using mixed models for repeated measures.

Results:
Participants receiving BUP-XR (n = 389) versus placebo (n = 98) had significantly greater changes from baseline on the EQ-5D-5L index (300/300 mg: difference = 0.0636, P
= 0.003), EQ-5D-5L visual analog scale (300/300 mg: difference = 5.9, P
= 0.017; 300/100 mg: difference = 7.7, P
= 0.002), and SF-36v2 physical component summary score (300/300 mg: difference = 3.8, P
< 0.001; 300/100 mg: difference = 3.2, P
= 0.002). Satisfaction was significantly higher for participants receiving BUP-XR 300/300 mg (88%, P < 0.001) and 300/100 mg (88%, P < 0.001) than placebo (46%). Employment and percentage of insured participants increased by 10.8% and 4.1% with BUP-XR 300/300 mg and 10.0% and 4.7% with 300/100 mg but decreased by 12.6% and 8.4% with placebo. Participants receiving BUP-XR compared with placebo had significantly fewer hospital days per person-year observed.

Conclusions:
These results show the feasibility of measuring patient-centered life changes in substance use disorder clinical studies. Participants receiving up to 6 monthly injections of BUP-XR, compared with placebo, reported better health, increased medication satisfaction, increased employment, and decreased healthcare utilization.
Factors Associated With Accuracy of Self-Assessment Compared With Tested Non–English Language Proficiency Among Primary Care Providers
Authors: Diamond Lisa , Toro Bejarano Marcela , Chung Sukyung , Ferguson Warren , Gonzalez Javier , Genoff Garzon Margaux , Mujawar Imran , Gany Francesca 
Published: March 2019

Background:
There are no accepted best practices for clinicians to report their non–English language (NEL) fluencies. Language discordance between patients with limited English proficiency and their clinicians may contribute to suboptimal quality of care.

Objectives:
To compare self-assessed clinician NEL proficiency with a validated oral language proficiency test. To identify clinician characteristics associated with self-assessment accuracy.

Subjects:
Primary care providers from California and Massachusetts.

Research Design:
We surveyed 98 clinicians about demographics and their NEL self-assessment using an adapted version of the Interagency Language Roundtable (ILR) scale followed by an oral proficiency interview: The Clinician Cultural and Linguistic Assessment (CCLA). We compared the ILR to the CCLA and analyzed factors associated with the accuracy of self-assessment.

Results:
Ninety-eight primary care providers participated: 75.5% were women, 62.2% were white, and Spanish was the most common NEL reported (81.6%). The average CCLA score was 78/100 with a 70% passing-rate. There was a moderate correlation between the ILR and CCLA (0.512; P<0.0001). Participants whose self-reported levels were “fair” and “poor” had a 0% pass-rate and 100% who self-reported “excellent” passed the CCLA. Middle ILR levels showed a wider variance. Clinicians who reported a NEL other than Spanish and whose first language was not English were more likely to accurately self-assess their abilities.

Conclusions:
Self-assessment showed a moderate correlation with the validated CCLA test. Additional testing may be required for clinicians at the middle levels. Clinicians whose native languages were not English and those using languages other than Spanish with patients may be more accurate in their self-assessment.
Hospital Volume and Operative Mortality for General Surgery Operations Performed Emergently in Adults
Authors: Becher Robert D. , DeWane Michael P. , Sukumar Nitin , Stolar Marilyn J. , Gill Thomas M. , Maung Adrian A. , Schuster Kevin M. , Davis Kimberly A. 
Published: March 2019

Objective:
This study aimed to answer 2 questions: first, to what degree does hospital operative volume affect mortality for adult patients undergoing 1 of 10 common emergency general surgery (EGS) operations? Second, at what hospital operative volume threshold will nearly all patients undergoing an emergency operation realize the average mortality risk?

Background:
Nontrauma surgical emergencies are an underappreciated public health crisis in the United States; redefining where such emergencies are managed may improve outcomes. The field of trauma surgery established regionalized systems of care in part because studies demonstrated a clear relationship between hospital volume and survival for traumatic emergencies. Such a relationship has not been well-studied for nontrauma surgical emergencies.

Methods:
Retrospective cohort study of all acute care hospitals in California performing nontrauma surgical emergencies. We employed a novel use of an ecological analysis with beta regression to investigate the relationship between hospital operative volume and mortality.

Results:
A total of 425 acute care hospitals in California performed 165,123 EGS operations. Risk-adjusted mortality significantly decreased as volume increased for all 10 EGS operations (P < 0.001 for each); the relative magnitude of this inverse relationship differed substantially by procedure. Hospital operative volume thresholds were defined and varied by operation: from 75 cases over 2 years for cholecystectomy to 7 cases for umbilical hernia repair.

Conclusions:
Survival rates for nontrauma surgical emergencies were improved when operations were performed at higher-volume hospitals. The use of ecological analysis is widely applicable to the field of surgical outcomes research.
Stratification of Postsurgical Computed Tomography Surveillance Based on the Extragastric Recurrence of Early Gastric Cancer
Authors: Seo Nieun , Han Kyunghwa , Hyung Woo Jin , Chung Yong Eun , Park Chan Hyuk , Kim Jie-Hyun , Lee Sang Kil , Kim Myeong-Jin , Noh Sung Hoon , Lim Joon Seok 
Published: March 2019

Objective:
To stratify the postsurgical computed tomography (CT) surveillance based on a risk-scoring system for predicting extragastric recurrence after surgical resection of early gastric cancer (EGC).

Summary of Background Data:
Postsurgical CT surveillance should not be routinely performed in all patients because of the low incidence of extragastric recurrence and potential risk of radiation exposure.

Methods:
Data from 3162 patients who underwent surgical resection for EGC were reviewed to develop a risk-scoring system to predict extragastric recurrence. Risk scores were based on the predictive factors for extragastric recurrence, which were determined using Cox proportional hazard regression model. The risk-scoring system was validated by Uno censoring adjusted C-index. External validation was performed using an independent dataset (n = 430).

Results:
The overall incidence of extragastric recurrence was 1.4% (44/3162). Five risk factors (lymph node metastasis, indications for endoscopic resection, male sex, positive lymphovascular invasion, and elevated macroscopic type), which were significantly associated with extragastric recurrence, were incorporated into the risk-scoring system, and the patients were categorized into 2 risk groups. The 10-year extragastric recurrence-free survival differed significantly between low- and high-risk groups (99.7% vs 96.5%; P < 0.001). The predictive accuracy of the risk-scoring system in the development cohort was 0.870 [Uno C-index; 95% confidence interval (95% CI), 0.800–0.939]. Discrimination was good after internal (0.859) and external validation (0.782, 0.549–1.000).

Conclusion:
This risk-scoring system might be useful to predict extragastric recurrence of EGC after curative surgical resection. We suggest that postsurgical CT surveillance to detect extragastric recurrence should be avoided in the low-risk group.
A widespread toxin-antitoxin system exploiting growth control via alarmone signalling
Authors: Jimmy Steffi , Saha Chayan Kumar , Stavropoulos Constantine , Oliveira Sofia Raquel Alves , Kurata Tatsuaki , Koh Alan , Cepauskas Albinas , Takada Hiraku , Tenson Tanel , Strahl Henrik , Garcia-Pino Abel , Hauryliuk Vasili , Atkinson Gemma C. 
Published: March 2019

ABSTRACTUnder stressful conditions, bacterial RelA-SpoT Homologue (RSH) enzymes synthesise the alarmone (p)ppGpp, a nucleotide messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope with stress, and at high concentrations inhibits the process of protein synthesis and bacterial growth to save and redirect resources until conditions improve. Single domain Small Alarmone Synthetases (SASs) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the hydrolysis (HD) domain and regulatory C-terminal domains of the long RSHs such as Rel, RelA and SpoT. We have discovered that multiple SAS subfamilies can be encoded in broadly distributed conserved bicistronic operon architectures in bacteria and bacteriophages that are reminiscent of those typically seen in toxin-antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), with neutralisation by the protein products of six neighbouring antitoxin genes. The toxicity ofCellulomonas marinaToxSAS FaRel is mediated by alarmone accumulation combined with depletion of cellular ATP and GTP pools, and this is counteracted by its HD domain-containing antitoxin. Thus, the ToxSAS-antiToxSAS system is a novel TA paradigm comprising multiple different antitoxins that exemplifies how ancient nucleotide-based signalling mechanisms can be repurposed as TA modules during evolution, potentially multiple times independently.
Multi-task learning predicts drug combination synergy in cells and in the clinic
Authors: Gilvary Coryandar , Dry Jonathan R , Elemento Olivier 
Published: March 2019

ABSTRACTCombination therapies for various cancers have been shown to increase efficacy, lower toxicity, and circumvent resistance. However, despite the promise of combinatorial therapies, the biological mechanisms behind drug synergy have not been fully characterized, and the systematic testing of all possible synergistic therapies is experimentally infeasible due to the sheer volume of potential combinations. Here we apply a novel big data approach in the evaluation and prediction of drug synergy by using the recently released NCI-ALMANAC. We found that each traditional drug synergy metric (Bliss, Loewe, ZIP, HSA, ALMANAC Score) identified unique synergistic drug pairs with distinct underlying joint mechanisms of action. Leveraging these findings, we developed a suite of context specific drug synergy predictive models for each distinct synergy type and achieved significant predictive performance (AUC = 0.89-0.953). Furthermore, our models accurately identified clinically tested drug pairs and characterized the clinical relevance of each drug synergy metric, with Bliss Independence capturing clinically tested combinations best. Our findings demonstrate that drug synergy can be obtained from numerous unique joint mechanisms of action, captured by different synergy metrics. Additionally, we show that drug synergy, of all kinds, can be predicted with high degrees of accuracy with significant clinical potential. This breakthrough understanding of joint mechanisms of action will allow for the design of rational combinatorial therapeutics on a large scale, across various cancer types.
Publicly available transcriptomes provide the opportunity for dual RNA-Seq meta-analysis inPlasmodiuminfection
Authors: Mukherjee Parnika , Burgio Gaétan , Heitlinger Emanuel 
Published: March 2019

AbstractDual RNA-Seq is the simultaneous transcriptomic analysis of interacting symbionts, for example, in malaria. Potential cross-species interactions identified by correlated gene expression might highlight interlinked signaling, metabolic or gene regulatory pathways in addition to physically interacting proteins. Often, malaria studies address one of the interacting organisms – host or parasite – rendering the other “contamination”. Here we perform a meta-analysis using such studies for cross-species expression analysis.We screened experiments for gene expression from host andPlasmodium. Out of 171 studies inHomo sapiens, Macaca mulattaandMus musculus, we identified 63 potential studies containing host and parasite data. While 16 studies (1950 samples) explicitly performed dual RNA-Seq, 47 (1398 samples) originally focused on one organism. We found 915 experimental replicates from 20 blood studies to be suitable for co-expression analysis and used orthologs for meta-analysis across different host-parasite systems. Centrality metrics from the derived gene expression networks correlated with gene essentiality in the parasites. We found indications of host immune response to elements of thePlasmodiumprotein degradation system, an antimalarial drug target. We identified well-studied immune responses in the host with our co-expression networks as our approach recovers known broad processes interlinked between hosts and parasites in addition to individual host and parasite protein associations.The set of core interactions represents commonalities between human malaria and its model systems for prioritization in laboratory experiments. Our approach might also allow insights into the transferability of model systems for different pathways in malaria studies.ImportanceMalaria still causes about 400,000 deaths a year and is one the most studied infectious diseases. The disease is studied in mice and monkeys as lab models to derive potential therapeutic intervention in human malaria. Interactions betweenPlasmodiumspp. and its hosts are either conserved across different host-parasite systems or idiosyncratic to those systems. Here we use correlation of gene expression from different RNA-Seq studies to infer common host-parasite interactions across human, mouse and monkey studies. We, firstly, find a set of very conserved interactors, worth further scrutiny in focussed laboratory experiments. Secondly, this work might help assess to which extent experiments and knowledge on different pathways can be transferred from models to humans for potential therapy.
The Antagonism of Folate Receptor by the Integrase Inhibitor Dolutegravir: Developmental Toxicity Reduction by Supplemental Folic Acid
Authors: Cabrera Robert M. , Souder Jaclyn P. , Steele John W. , Yeo Lythou , Tukeman Gabriel , Gorelick Daniel A. , Finnell Richard H. 
Published: March 2019

ABSTRACTHuman immunodeficiency virus (HIV) integrase inhibitors are increasingly being used for antiretroviral therapy (ART), and dolutegravir (DTG/Tivicay) has emerged as a leading core agent. In 2018, the Tsepamo study reported a 6- to 9-fold increase for neural tube defect (NTD) risk among the offspring of mothers receiving DTG during early gestation. Maternal folate (vitamin B9) status is the largest known modifier of NTD risk, so we evaluated folate-related mechanisms of action and the critical period for DTG developmental toxicity. Folate receptor (FOLR1) binding studies indicate DTG is a non-competitive FOLR1 antagonist at therapeutic concentrations.In vitrotesting indicates calcium (2mM) increases FOLR1-folate interactions and alters DTG-FOLR1-folate interactions and cytotoxicity. DTG does not inhibit downstream folate metabolism by dihydrofolate reductase (DHFR). Early embryonic exposure to DTG is developmentally toxic in zebrafish, and supplemental folic acid can mitigate DTG developmental toxicity. The results from these studies are expected to inform and guide future animal models and clinical studies of DTG-based ART in women of childbearing age.
Brain meta-state transitions demarcate thoughts across task contexts, exposing the mental noise of trait neuroticism
Authors: Tseng Julie , Poppenk Jordan 
Published: March 2019

SummaryUsing new methods to capture streams of neural meta-state transitions in single participants, we characterize the psychological meaning of these regular neural events. Similar to past group-average-based analyses, participants’ individual transition streams aligned to meaningful events during movie-viewing. However, our individual-based approach also afforded observation of participants’ idiosyncratic transition timing at rest. Across these two dramatically different task contexts, transitions featured similar trait-like frequency, concurrence with activation of regions associated with spontaneous thought, and suppression by attention regions. Based on this generalization, as well as the centrality of semantics to thought, we argue transitions serve as a general, implicit neurobiological marker of new thoughts, and that their frequency therefore approximates participants’ mentation rate. Finally, to contribute convergent validity and illustrate the utility of our approach for thought dynamics, we regressed resting transition rate and movie-viewing group temporal conformity against trait neuroticism, yielding a first neural confirmation of the “mental noise” theory.
Regulation of antimycin biosynthesis is controlled by the ClpXP protease
Authors: Bilyk Bohdan , Kim Sora , Fazal Asif , Baker Tania A. , Seipke Ryan F. 
Published: March 2019

AbstractThe survival of any microbe relies upon its ability to respond to environmental change. Use of Extra Cytoplasmic Function (ECF) RNA polymerase sigma (σ) factors is a major strategy enabling dynamic responses to extracellular signals. Streptomyces species harbor a large number of ECF σ factors; nearly all of which regulate genes required for morphological differentiation and/or response to environmental stress, except for σAntA, which regulates starter-unit biosynthesis in the production of antimycin, an anticancer compound. Unlike a canonical ECF σ factor, whose activity is regulated by a cognate anti-σ factor, σAntA is an orphan, raising intriguing questions about how its activity may be controlled. Here, we reconstitute in vitro ClpXP proteolysis of σAntA, but not a variant lacking a C-terminal di-alanine motif. Furthermore, we show that the abundance of σAntAin vivo is enhanced by removal of the ClpXP recognition sequence, and that levels of the protein rise when cellular ClpXP protease activity is abolished. These data establish direct proteolysis as an alternative and thus far unique control strategy for an ECF RNA polymerase σ factor and expands the paradigmatic understanding of microbial signal transduction regulation.ImportanceNatural products produced by Streptomyces species underpin many industrially- and medically-important compounds. However, the majority of the ~30 biosynthetic pathways harboured by an average species are not expressed in the laboratory. This undiscovered biochemical diversity is believed to comprise an untapped resource for natural products drug discovery. A major roadblock preventing the exploitation of unexpressed biosynthetic pathways is a lack of insight into their regulation and limited technology for activating their expression. Our findings reveal that the abundance of σAntA, which is the cluster-situated regulator of antimycin biosynthesis, is controlled by the ClpXP protease. These data link proteolysis to the regulation of natural product biosynthesis for the first time and we anticipate that this will emerge as a major strategy by which actinobacteria regulate production of their natural products. Further study of this process will advance understanding of how expression of secondary metabolism is controlled and will aid pursuit of activating unexpressed biosynthetic pathways.
The sequence of the extruded non-template strand determines the architecture of R-loops
Authors: Carrasco-Salas Yeraldinne , Malapert Amélie , Sulthana Shaheen , Molcrette Bastien , Chazot-Franguiadakis Léa , Bernard Pascal , Chédin Frédéric , Faivre-Moskalenko Cendrine , Vanoosthuyse Vincent 
Published: March 2019

ABSTRACTThree-stranded R-loop structures have been associated with genomic instability phenotypes. What underlies their wide-ranging effects on genome stability remains poorly understood. Here we combined biochemical and atomic force microscopy approaches with single molecule R-loop footprinting to demonstrate that R-loops formed at the model Airn locus in vitro adopt a defined set of three-dimensional conformations characterized by distinct shapes and volumes, which we call R-loop objects. Interestingly, we show that these R-loop objects impose specific physical constraints on the DNA, as revealed by the presence of stereotypical angles in the surrounding DNA. Biochemical probing and mutagenesis experiments revealed that the formation of R-loop objects at Airn is dictated by the sequence of the extruded non-template strand, suggesting that R-loops possess intrinsic sequence-driven properties. Consistent with this, we show that R-loops formed at the fission yeast gene sum3 do not form detectable R-loop objects. Our results reveal that R-loops differ by their architectures and that the organization of the non-template strand is a fundamental characteristic of R-loops, which could explain that only a subset of R-loops is associated with replication-dependent DNA breaks.