bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity in efflux pump expression predisposes antibiotic-resistant cells to mutation
Authors: El Meouche Imane , Dunlop Mary J. 
Published: November 2018

Efflux pumps and mutation
Antibiotic resistance is an alarming and growing challenge. Bacteria show great heterogeneity in growth and mutation rates. Such variability allows some cells to persist during transient antibiotic exposure. During this persistent phase, mutations accumulate, which can result in selection for full-blown antibiotic resistance. El Meouche and Dunlop found that increased expression of efflux pumps on some cells affords them some relief from antibiotic toxicity. But up-regulating efflux pumps is costly for the bacteria, reducing growth rate and expression of MutS, a protein involved in DNA mismatch repair. These changes thus lift the lid on increased levels of bacterial mutation.

Science
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Two-dimensional Schrödinger operators with point interactions: Threshold expansions, zero modes and Lp-boundedness of wave operators
Authors: Cornean Horia D. , Michelangeli Alessandro , Yajima Kenji 
Published: November 2018

We study the threshold behavior of two-dimensional Schrödinger operators with finitely many local point interactions. We show that the resolvent can either be continuously extended up to the threshold, in which case we say that the operator is of regular type, or it has singularities associated with [Formula: see text] or [Formula: see text]-wave resonances or even with an embedded eigenvalue at zero, for whose existence we give necessary and sufficient conditions. An embedded eigenvalue at zero may appear only if we have at least three centers.When the operator is of regular type, we prove that the wave operators are bounded in [Formula: see text] for all [Formula: see text]. With a single center, we always are in the regular type case.
Molecular characterization of a precision-cut rat liver slice model for the evaluation of antifibrotic compounds
Authors: Huang Xinqiang , Cai Hong , Ammar Ron , Zhang Yan , Wang Yihe , Ravi Kandasamy , Thompson John , Jarai Gabor 
Published: November 2018

Precision-cut liver tissue slice (PCLS) contains all major cell types of the liver parenchyma and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study liver fibrosis and test the antifibrotic effect of experimental compounds in a physiological environment. In this study using RNA sequencing, we demonstrated that various pathways functionally related to fibrotic mechanisms were dysregulated in PCLSs derived from rats subjected to bile duct ligation. The activin receptor-like kinase-5 (Alk5) inhibitor SB525334, nintedanib, and sorafenib each reversed a subset of genes dysregulated in fibrotic PCLSs, and of those genes we identified 608 genes whose expression was reversed by all three compounds. These genes define a molecular signature characterizing many aspects of liver fibrosis pathology and its attenuation in the model. A panel of 12 genes and 4 secreted biomarkers including procollagen I, hyaluronic acid (HA), insulin-like growth factor binding protein 5 (IGFBP5), and WNT1-inducible signaling pathway protein 1 (WISP1) were further validated as efficacy end points for the evaluation of antifibrotic activity of experimental compounds. Finally, we showed that blockade of αV-integrins with a small molecule inhibitor attenuated the fibrotic phenotype in the model. Overall, our results suggest that the rat fibrotic PCLS model may represent a valuable system for target validation and determining the efficacy of experimental compounds. NEW & NOTEWORTHY We investigated the antifibrotic activity of three compounds, the activin receptor-like kinase-5 (Alk5) inhibitor SB525334, nintedanib, and sorafenib, in a rat fibrotic precision-cut liver tissue slice model using RNA sequencing analysis. A panel of 12 genes and 4 secreted biomarkers including procollagen I, hyaluronic acid (HA), insulin-like growth factor binding protein 5 (IGFBP5), and WNT1-inducible signaling pathway protein 1 (WISP1) were then established as efficacy end points to validate the antifibrotic activity of the αV-integrin inhibitor CWHM12. This study demonstrated the value of the rat fibrotic PCLS model for the evaluation of antifibrotic drugs.
The Impact of Cerebral Atherosclerosis According to Location on Prognosis after Coronary Artery Bypass Grafting
Authors: Lee Eun-Jae , Chung Cheol-Hyun , Choi Kyoung-Hyo , Lee Jae-Won , Choo Suk-Jung , Jung Sung-Ho , Kang Dong-Wha , Kim Jong S. , Kwon Sun U. 
Published: November 2018

<b><i>Background:</i></b> In the previous prospective observational study, we found that cerebral atherosclerosis is an independent predictor of acute stroke after coronary artery bypass grafting (CABG). However, it is unknown whether intracranial cerebral atherosclerosis (ICAS) is important as much as extracranial cerebral atherosclerosis (ECAS) in estimating the risk of post-CABG adverse events. Extending the previous study, we aimed to investigate the immediate and long-term prognostic value of the location of cerebral atherosclerosis in CABG patients. <b><i>Methods:</i></b> This follow-up study of previously reported prospective cohort included 1,367 consecutive patients who received CABG between 2004 and 2007. All patients underwent preoperative magnetic resonance angiography (MRA) to assess intracranial and ECAS, both defined by significant steno-occlusion (≥50%). Participants were classified into 4 groups according to the location of cerebral atherosclerosis: no cerebral atherosclerosis, ECAS only, ICAS only, and ECAS + ICAS. Post-CABG stroke within 14 days (immediate outcome) and mortality (long-term outcome) following CABG were compared between the groups. Survival data for all participants through June 2016 were obtained from the Korean National Registry of Vital Statistics. The Cox proportional hazards model was used to estimate the hazard ratio (HR) of post-CABG stroke and mortality; patients lacking cerebral atherosclerosis were defined as the reference group. <b><i>Results:</i></b> The median follow-up duration after CABG was 9.2 years (interquartile range 8.4–10.2 years). Of the participants, 278 (20.3%) patients had ICAS only, while 269 (19.7%) and 347 (25.4%) showed ECAS only and ECAS + ICAS, respectively, in their preoperative MRA. Having ICAS only (HR 5.07; 95% CI 1.37–18.75; <i>p</i> = 0.015) and having ECAS + ICAS (HR 8.43; 95% CI, 2.48–28.61; <i>p</i> = 0.001) independently predicted the immediate stroke, whereas being with ECAS only did not (HR 1.71; 95% CI 0.35–8.50; <i>p</i> = 0.509). Conversely, ICAS-only status was not independently associated with long-term mortality (HR 1.22; 95% CI 0.90–1.65; <i>p</i> = 0.207), whereas ECAS-only status (HR 1.42; 95% CI 1.05–1.90; <i>p</i> = 0.021) and ECAS + ICAS status (HR 1.58; 95% CI 1.20–2.07; <i>p</i> = 0.001) showed independent associations. <b><i>Conclusions:</i></b> Over 10 years of follow-up, cerebral atherosclerosis significantly associated with the development of adverse outcomes after CABG. The prognostic value of ICAS might be different from that of ECAS; immediate post-CABG stroke was more closely associated with ICAS, whereas there was a closer association between long-term post-CABG mortality and ECAS.
Switch-associated adverse events: focus on olanzapine
Authors: Xu Lily , Krishnaswamy Saroja 
Published: November 2018

Objectives: Switching between different antipsychotic therapies is a frequent occurrence in the management of patients with schizophrenia and other psychotic disorders. This paper provides a review of the principles of antipsychotic switching and discusses pharmacological principles underlying adverse events that occur while switching olanzapine to another antipsychotic medication. It offers suggestions for management of switch-associated adverse events in clinical settings. Conclusions: Few publications explore olanzapine switch-related adverse events, the underlying pharmacological principles and appropriate switching strategies to minimise the risk of adverse events. There is still a need for further studies to verify existing knowledge and assist in the development of ‘gold standard’ guidelines that outline appropriate switching strategies and duration of the switching process to reduce and avoid adverse events.
Recent Updates in the Pharmacological Management of Sepsis and Septic Shock: A Systematic Review Focused on Fluid Resuscitation, Vasopressors, and Corticosteroids
Authors: Allen John M. , Feild Carinda , Shoulders Bethany R. , Voils Stacy A. 
Published: November 2018

Objective: Describe recent developments in the pharmacological management of sepsis and septic shock, focusing on fluid resuscitation, vasopressors, and corticosteroids. Data Sources: A literature search limited to randomized controlled trials written in the English language reporting mortality and other clinically relevant outcomes that were published from July 1, 2016, to August 31, 2018, in patients aged ≥ 18 years. Titles and abstracts were reviewed for relevance. References for pertinent review articles were also reviewed. Study Selection and Data Extraction: Relevant randomized controlled trials conducted in patients meeting the pre-defined inclusion criteria were considered for inclusion. Data Synthesis: From an initial search that identified 147 studies, 14 original research studies met inclusion criteria and were included in this review. Risk of bias (ROB) was assessed using the Revised Cochrane ROB assessment tool, with most included studies having a low ROB. Relevance to Patient Care and Clinical Practice: Sepsis and septic shock pose a significant burden on public health. Despite advances in our understanding of sepsis, mortality remains unacceptably high. Recent developments in the pharmacological management of septic shock have focused on determining optimal composition and dosage of fluid resuscitation, enhanced use of vasopressor therapy, and clarifying the role of corticosteroids. This systematic review will provide recommendations for application to practice focusing on recent research on these topics. Conclusions: Although recent developments in the pharmacological management of sepsis are encouraging, clinicians must be keen to utilize patient-specific factors to guide therapy and continue to strive to address the remaining unanswered questions.
Treatment dilemmas in asymptomatic children with primary hemophagocytic lymphohistiocytosis
Authors: Lucchini Giovanna , Marsh Rebecca , Gilmour Kimberly , Worth Austen , Nademi Zohreh , Rao Anupama , Booth Claire , Amrolia Persis , Silva Juliana , Chiesa Robert , Wynn Robert , Lehmberg Kai , Astigarraga Itziar , Güngör Tayfun , Stary Jan , Moshous Despina , Ifversen Marianne , Zinn Daniel , Jordan Michael , Kumar Ashish , Yasumi Takahiro , Veys Paul , Rao Kanchan 
Published: November 2018

Key Points
Preemptive allogeneic stem cell transplantation improves prognosis of asymptomatic children genetically predisposed to primary HLH.
Comparative effects of vitamin D and vitamin C supplementations with and without endurance physical activity on metabolic syndrome patients: a randomized controlled trial
Authors: Farag Halgord Ali M. , Hosseinzadeh-Attar Mohammad Javad , Muhammad Belal A. , Esmaillzadeh Ahmad , Bilbeisi Abdel Hamid El 
Published: November 2018

Abstract
Objective
Vitamin D and C levels have inverse relation with the metabolic syndrome components and they are used as antioxidant supplements during enduring metabolic activities. In the present study, we hypothesized that the intake of vitamin D and/or C with endurance physical activity might reduce the risk of metabolic syndrome.

Methods
A randomized control study recruited 180 participants of both genders, aged between 30 and 50 years. The participants were assigned into six groups receiving different doses of vitamin D or vitamin C with or without physical activities. Data were collected over a period of 3 months, and the results were analyzed using SPSS version 20.

Results
Variations in the effect of the supplements on various body variables including: Fasting plasma glucose, total cholesterol, low-density lipoprotein cholesterol and blood pressure, showed that vitamin D has more influence compared to vitamin C. However, vitamin D and C supplements do not have any effect on weight when consumers are undergoing endurance physical exercise. But vitamin C consumer group has more effect in waist circumference, triglyceride, and high-density lipoprotein, as compared to vitamin D consumer group.

Conclusion
We conclude that, consumption of vitamin D or vitamin C supplements may improves the life of metabolic syndrome patients. However, the combination of physical activities and vitamin supplements maximize the effect, and this combination should be recommended.
Trial registration WHO-ICTRP IRCT20161110030823N2. Registered 01 February 2018. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=IRCT20161110030823N2
Camera calibration with coplanar conics: a unified explanation and ambiguity analysis
Authors: Cai Shen , Wu Zhanhao 
Published: November 2018

Abstract
In this paper, we propose a two-step method to give a unified explanation of camera calibration with two coplanar conics. Various kinds of conics-based patterns in which often two parameters are unknown have been studied in previous literatures. The key in such algorithms is to adopt different strategies to compute the world-to-image projective transformation (also called 2D homography). In the first step of our method, we show that two unknown parameters can always be computed in general cases by utilizing the underlying constraints on all parameters through the projective transformation (mathematically called projective invariants). The accompanied ambiguity problem is that the solutions of the unknown parameters are multiple. In the second step, the four intersection points (real or complex) of two totally known conics are utilized to compute the homography. The ambiguity in this step arises from the point correspondence problem. This results in multiple possibilities of correspondences followed by the ambiguous homographies. After analyzing the reasons of the two kinds of ambiguities, we apply the Centre Circle constraint to completely remove them. Finally, the experiments are shown to validate the proposed technique.
Hoarding revisited: there is light at the end of the living room
Authors: Pertusa Alberto , Lopez Gaston Romina , Choudry Abid 
Published: November 2018

SUMMARYSince 2013, hoarding disorder has been recognised as a standalone diagnosis in the DSM, affecting an estimated 2–6% of the general population. This article outlines the arguments for and against this separate classification and considers the differentiation of hoarding disorder from normative collecting. It then discusses aetiology, assessment, course and treatment (both psychological and pharmacological interventions). It concludes with a discussion of ethical and legal considerations, in particular the fact that the inclusion of hoarding disorder as a distinct diagnosis in DSM-5 confers specific protections for people with the disorder under the Equality Act 2010.LEARNING OBJECTIVES•Be able to define the criteria of hoarding disorder•Be able to recognise the difference between hoarding and collecting•Understand potential treatment options for patients with hoarding disorderDECLARATION OF INTERESTNone.
Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial
Authors: Kluger Harriet M. , Chiang Veronica , Mahajan Amit , Zito Christopher R. , Sznol Mario , Tran Thuy , Weiss Sarah A. , Cohen Justine V. , Yu James , Hegde Upendra , Perrotti Elizabeth , Anderson Gail , Ralabate Amanda , Kluger Yuval , Wei Wei , Goldberg Sarah B. , Jilaveanu Lucia B. 
Published: November 2018

Purpose Pembrolizumab is active in melanoma, but activity in patients with untreated brain metastasis is less established. We present long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial ( ClinicalTrials.gov identifier: NCT02085070). Patients and Methods We enrolled 23 patients with melanoma with one or more asymptomatic, untreated 5- to 20-mm brain metastasis not requiring corticosteroids; 70% of patients had prior systemic therapy. Pembrolizumab was administered for up to 24 months. Brain metastasis response, the primary end point, was assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST). Pretreatment tumors were analyzed for T-cell infiltrate and programmed death ligand 1. Results Six patients (26%) had a brain metastasis response. Eight patients (35%) did not reach a protocol evaluation scan and were unevaluable for brain metastasis response as a result of progression or need for radiation. Brain metastasis and systemic responses were concordant, with all ongoing at 24 months. The median progression-free and overall survival times were 2 and 17 months, respectively. Eleven patients (48%) were alive at 24 months. This included three unevaluable patients. One of these three patients had hemorrhaged, and two had symptoms from perilesional edema requiring radiosurgery, but all three patients remained on commercial pembrolizumab more than 24 months later. None of the 24-month survivors received subsequent BRAF inhibitors. Neurologic adverse events occurred in 65% of patients; all adverse events but one were grade 1 or 2. Three patients had seizures, which were treated with anticonvulsants. Most responders had higher pretreatment tumor CD8 cell density and programmed death ligand 1 expression, whereas all nonresponders did not. Conclusion Pembrolizumab is active in melanoma brain metastases with acceptable toxicity and durable responses. Multidisciplinary care is required to optimally manage patients with brain metastases, including consideration of radiation to large or symptomatic lesions, which were excluded in this trial. Two-year survival was similar to patients without brain metastasis treated with anti–programmed cell death 1 agents. Concordant brain and extracerebral responses support use of pembrolizumab to treat small, asymptomatic brain metastases.
Factors Associated With Follow-Up Care Among Women With Early-Stage Breast Cancer
Authors: Quyyumi Farah F. , Wright Jason D. , Accordino Melissa K. , Buono Donna , Law Cynthia W. , Hillyer Grace C. , Neugut Alfred I. , Hershman Dawn L. 
Published: November 2018

PURPOSE: Follow-up guidelines vary widely among national organizations for patients with early-stage breast cancer treated with curative intent. We sought to evaluate the patterns and predictors of provider follow-up care within the first 5 years after diagnosis. METHODS: Using the SEER-Medicare linked data set, we evaluated patients who were diagnosed with stage I and II breast cancer who underwent breast-conserving surgery from 2002 to 2007 with follow-up until 2012. We defined discontinuation of follow-up as > 12 months from the previous physician visit without a visit claim from either a surgeon, medical oncologist, or radiation oncologist. We performed a multivariable logistic regression and Cox proportional hazards regression analysis to determine factors associated with the discontinuation of follow-up care. RESULTS: Of the 30,053 patients enrolled in our initial cohort, 25,781 (85.8%) saw a medical oncologist and 21,612 (71.9%) saw a radiation oncologist in the first year in addition to a surgeon. Over the 5 years, 6,302 patients (21.0%) discontinued follow-up visits. Discontinuation of physician visits increased with increasing age. Women with stage II cancer ( v stage I) were less likely to discontinue follow-up visits (odds ratio, 0.78; 95% CI, 0.73 to 0.83). Time to early discontinuation was greater for patients with hormone receptor–negative tumors (hazard ratio, 1.14; 95% CI, 1.05 to 1.24). Women who were diagnosed more recently were less likely to discontinue seeing any physician. CONCLUSION: Twenty-one percent of patients with early-stage breast cancer discontinued seeing any oncology provider over the 5 years after diagnosis. Coordination of follow-up care between oncology specialists may reduce discontinuation rates and increase clinical efficiency.
Tumor-Infiltrating Lymphocyte Function Predicts Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer
Authors: Kong Joseph Cherng Huei , Guerra Glen Robert , Millen Rosemary Magdalena , Roth Sara , Xu Huiling , Neeson Paul Joseph , Darcy Phillip Kevin , Kershaw Michael Henry , Sampurno Shienny , Malaterre Jordane , Liu David Shi Hao , Pham Toan Duc , Narasimhan Vignesh , Wang Minyu , Huang Yu-Kuan , Visvanathan Kumar , McCormick Jacob , Lynch Andrew Craig , Warrier Satish , Michael Michael , Desai Jayesh , Murray William , Mitchell Catherine , Ngan Samuel , Phillips Wayne Allen , Heriot Alexander Graham , Ramsay Robert George 
Published: November 2018

Purpose The presence of tumor-infiltrating lymphocytes (TILs) in tumors is superior to conventional pathologic staging in predicting patient outcome. However, their presence does not define TIL functionality. Here we developed an assay that tests TIL cytotoxicity in patients with locally advanced rectal cancer before definitive treatment, identifying those who will obtain a pathologic complete response (pCR). We also used the assay to demonstrate the rescue of TIL function after checkpoint inhibition blockade (CIB). Patients and Methods Thirty-four consecutive patients were identified initially, with successful completion of the assay before surgery in those 17 patients who underwent full treatment. An in vitro cytotoxic assay of rectal cancer tumoroids cocultured with patient-matched TILs was established and validated. Newly diagnosed patients were recruited with pretreatment biopsy specimens processed within 1 month. Evaluation of TIL-mediated tumoroid lysis was performed by measuring the mean fluorescence intensity of cell death marker, propidium iodide. CIB (anti–programmed cell death protein 1 [anti–PD-1] antibody) response was also assessed in a subset of patient specimens. Results Six of the 17 patients achieved an objective pCR on final evaluation of the resected specimen after neoadjuvant chemoradiotherapy. Cytotoxic killing identified the pCR group with a higher mean fluorescence intensity (27,982 [95% CI, 25,340 to 30,625]) compared with the non-pCR cohort (12,428 [95% CI, 9,434 to 15,423]; p < .001). Assessment of the effectiveness of CIB revealed partial restoration of cytotoxicity in TILs with increased PD-1 expression with anti–PD-1 antibody exposure. Conclusion Evaluating TIL function can be undertaken within weeks of the diagnostic biopsy, affording the potential to alter patient management decisions and refine selection for a watch-and-wait protocol. This cytotoxic assay also has the potential to serve as a platform to assist in the additional development of CIB.