bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methadone and buprenorphine pharmacokinetics and pharmacodynamics when coadministered with fostemsavir to opioid‐dependent, human immunodeficiency virus seronegative participants
Authors: Moore Katy , Magee Mindy , Sevinsky Heather , Chang Ming , Lubin Susan , Myers Elsa , Ackerman Peter , Llamoso Cyril 
Published: April 2019

AimsRegional human immunodeficiency virus (HIV) prevalence rates are high in people with history of injection drug use, including those managed with maintenance opioids. Fostemsavir (FTR) is an oral prodrug of temsavir, a first‐in‐class attachment inhibitor that binds HIV‐1 gp120, preventing initial HIV attachment and entry into host immune cells. Here we determine the impact of FTR on the pharmacokinetics of opioids methadone (MET: R‐, S‐ and total) or buprenorphine and norbuprenorphine (BUP and norBUP) when coadministered.MethodsStudy 206216 (NCT02666001) was a Phase I, open‐label study, assessing the effect of FTR 600 mg (extended‐release formulation) twice daily on pharmacokinetics of MET or BUP and norBUP, in non‐HIV‐infected participants on stable maintenance therapy with MET (40–120 mg; n = 16) or BUP plus naloxone (8–24 mg plus 2–6 mg; n = 16); pharmacodynamic response was assessed using standard opioid rating scales.ResultsFollowing coadministration with FTR, dose‐normalized MET (R‐, S‐ and total) exposures (maximum concentration in plasma, area under the plasma concentration–time curve over the dosing interval and concentration in plasma at 24 hours) increased 9–15% and BUP and norBUP exposures increased 24–39%. The 90% confidence interval ranges for MET (1.01–1.21) and BUP and norBUP (1.03–1.69) were within respective no‐effect ranges (0.7–1.43 and 0.5–2.0). Opioid pharmacodynamic scores were similar with and without MET/BUP with no symptoms of withdrawal/overdose; no new safety signal for FTR when combined with a stable opioid regimen.ConclusionsFTR did not impact MET and had no clinically significant impact on BUP pharmacokinetics. Standardized assessments of opioid pharmacodynamics were unchanged throughout FTR administration with MET or BUP. FTR can be administered with MET or BUP without dose adjustment.
Dynamics of circulating vascular endothelial growth factor‐A predict benefit from antiangiogenic cediranib in metastatic or recurrent cervical cancer patients
Authors: Zhou Cong , Taylor Sarah , Tugwood Jonathan , Simpson Kathryn , Jayson Gordon C. , Symonds Paul , Paul James , Davidson Susan , Carty Karen , McCartney Elaine , Rai Debbie , Dive Caroline , West Catharine 
Published: April 2019

AimsThere is a need for predictive and surrogate response biomarkers to support treatment with antiangiogenic vascular endothelial growth factor (VEGF) inhibitors. We aimed to identify a minimally‐invasive biomarker predicting benefit from cediranib pretreatment or early during treatment in patients with recurrent or metastatic cervical cancer.MethodsBlood samples were collected before treatment, during treatment and upon disease progression where appropriate from patients enrolled in CIRCCa, a randomised phase II trial of carboplatin and paclitaxel with or without cediranib. Plasma concentrations of VEGF‐A, VEGF‐receptor 2, Ang1 and Tie2 were measured using multiplex enzyme‐linked immunosorbent assay. Pretreatment and temporal changes of the biomarkers were investigated using proportional hazard regression and unsupervised clustering analysis.ResultsSamples (n = 556) from 52 patients were analysed. VEGF‐receptor 2 (P = .0006) and Tie2 (P = .04) were downregulated following cediranib, while VEGF‐A (P = .0025) was upregulated. High Eastern Cooperative Oncology Group performance status (P = .02, hazard ratio [HR] = 2.15, 95% confidence interval [CI] 1.13–4.09) and low pretreatment Tie2 concentrations (P = .003, HR = 0.57, 95%CI 0.39–0.83) were independent prognostic factors associated with reduced progression‐free survival. Two patterns of changes in VEGF‐A following cediranib were identified. Patients with elevated VEGF‐A in the first 3 treatment cycles, regardless of magnitude, had reduced progression‐free survival in the placebo arm but improved survival with the addition of cediranib (P = .019, HR = 0.13, 95% CI 0.02–0.71).ConclusionPatterns of early elevation in plasma VEGF‐A should be studied further as a potential biomarker to predict treatment benefit from cediranib.
Characteristics of severe life events, attachment style, and depression – Using a new online approach
Authors: Bifulco Antonia , Kagan Lisa , Spence Ruth , Nunn Stephen , Bailey‐Rodriguez Deborah , Hosang Georgina , Taylor Matthew , Fisher Helen L. 
Published: April 2019

ObjectivesSevere life events are established as provoking agents for depression in combination with vulnerability factors. Identifying features of severe events improves the prediction of disorder but are rarely utilized, mainly because life event research is increasingly dominated by self‐report checklists with no capacity for inferring such characteristics. This paper investigates the association of severe life events’ features with depression and insecure attachment styles using a new online measure of life events in a clinical and control sample.MethodsA total of 202 participants (75 clinical and 127 matched control participants), taken from an earlier national Depression Case Control genetic study and followed up after 12 years, completed the Computerised Life Events Assessment Record to assess characteristics of life events, the Vulnerable Attachment Style Questionnaire to measure attachment insecurity, and the General Health Questionnaire to measure depression.ResultsThe clinical group had higher self‐reported depression, severe life events, and insecure attachment style. They also reported more loss, danger, humiliation, and trauma severe events. Intra‐respondent analysis showed individuals experiencing these types of events were more likely to report depression. Insecure attachment style and severe life events were both significantly related to recent depression and history of depressive disorder. Anxious attachment style was significantly related to relationship events and bereavements, as well as severe loss or humiliation events, whereas avoidant style was not.ConclusionsIdentifying salient features of severe life events improves associations with depression and insecure attachment style. Utilizing a new online approach can aid research and clinical approaches for depression at low cost.Practitioner points

Salient features of severe life events (e.g., loss, humiliation) give insight into the potential impact on attachment vulnerability and depression.

Clinicians and researchers can use online methods to economically gain detailed life event information needed for clinical formulation and valid data on stressors.

The self‐reported scale for recent depression is only a proxy measure of clinical disorder, but the clinical group selection is a more robust criterion for depression history.
Validating process variables of sourcing in an assessment of multiple document comprehension
Authors: Hahnel Carolin , Kroehne Ulf , Goldhammer Frank , Schoor Cornelia , Mahlow Nina , Artelt Cordula 
Published: April 2019

BackgroundWith digital technologies, competence assessments can provide process data, such as mouse clicks with corresponding timestamps, as additional information about the skills and strategies of test takers. However, in order to use variables generated from process data sensibly for educational purposes, their interpretation needs to be validated with regard to their intended meaning.AimsThis study seeks to demonstrate how process data from an assessment of multiple document comprehension can be used to represent sourcing, which summarizes activities for the consideration of the origin and intention of documents. The investigated process variables were created according to theoretical assumptions about sourcing, and systematically tested for differences between persons, units (i.e., documents and items), and properties of the test administration.SampleThe sample included 310 German university students (79.4% female), enrolled in several bachelor's or master's programmes of the social sciences and humanities.MethodsRegarding the hierarchical data structure, the hypotheses were analysed with generalized linear mixed models (GLMM).ResultsThe results mostly revealed expected differences between individuals and units. However, unexpected effects of the administered order of units and documents were detected.ConclusionsThe study demonstrates the theory‐informed construction of process variables from log‐files and an approach for empirical validation of their interpretation. The results suggest that students apply sourcing for different reasons, but also stress the need of further validation studies and refinements in the operationalization of the indicators investigated.
Bendamustine for patients with indolent B cell lymphoproliferative malignancies including chronic lymphocytic leukaemia – an updated meta‐analysis
Authors: Vidal Liat , Gurion Ronit , Shargian Liat , Dreyling Martin , Gafter‐Gvili Anat 
Published: April 2019

SummaryThe question of which chemotherapy induction provides the best results for indolent lymphoma patients is yet unanswered. Different regimens have been compared, none of which has been shown to improve overall survival. The use of bendamustine is growing. A number of trials evaluated its efficacy for patients with indolent B‐cell lymphoid neoplasms, including chronic lymphocytic leukaemia (CLL). To evaluate the efficacy of bendamustine in that population we performed a systematic review and meta‐analysis of 9 randomised controlled trials (2726 patients). Bendamustine was compared to fludarabine‐containing regimens, CVP (cyclophosphamide, vincristine, prednisolone), CHOP (CVP+ doxorubicin) and chlorambucil. Due to insufficient reported data, six of the nine trials were included in analysis of overall survival. Bendamustine was associated with a prolonged overall survival, (hazard ratio 0·79, 95% confidence interval 0·65–0·95). Data regarding quality of life was reported for two trials, therefore too scarce to pool. The risk of neutropenia was reduced with bendamustine treatment compared to other chemotherapy. Bendamustine induction is an efficacious option for patients with indolent lymphoma, and CLL. Maintenance therapy was not evaluated after bendamustine induction, and potentially there is an interaction between the two. Chemotherapy‐free approach was shown to be efficacious for patients with CLL, while toxicity with that approach is not negligible.
Impaired cellular and humoral immunity is a feature of Diamond‐Blackfan anaemia; experience of 107 unselected cases in the United Kingdom
Authors: Iskander Deena , Roberts Irene , Rees Clare , Szydlo Richard , Alikian Mary , Neale Michael , Harrington Yvonne , Kelleher Peter , Karadimitris Anastasios , de la Fuente Josu 
Published: April 2019

SummaryDiamond‐Blackfan anaemia (DBA) is a rare bone marrow failure syndrome characterised by anaemia, congenital anomalies and cancer predisposition. Although infections are the second leading cause of mortality in non‐transplanted patients, immune function is largely unexplored. We identified quantitative deficits in serum immunoglobulins and/or circulating T, natural killer and B lymphocytes in 59 of 107 unselected patients (55·1%) attending our centre over a 7‐year period. Immune abnormalities were independent of ribosomal protein genotype and arose in both steroid‐treated and steroid‐untreated patients. In summary, these data highlight the high prevalence and spectrum of infections and immune defects in DBA.
Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor
Authors: Cecon Erika , Dam Julie , Luka Marine , Gautier Clément , Chollet Anne‐Marie , Delagrange Philippe , Danober Laurence , Jockers Ralf 
Published: April 2019

Background and PurposeProgressive dysfunction of cholinergic transmission is a well‐known characteristic of Alzheimer's disease (AD). Amyloid β (Aβ) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor α7 (α7nAChR). However, the mechanism underlying the effect of Aβ on α7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and characterize Aβ binding to α7nAChR, including the possibility of interfering with this interaction for therapeutic purposes.Experimental ApproachWe developed a specific and quantitative time‐resolved FRET (TR‐FRET)‐based binding assay for Aβ to α7nAChR and pharmacologically characterized this interaction.Key ResultsWe demonstrated specific and high‐affinity (low nanomolar) binding of Aβ to the orthosteric binding site of α7nAChR. Aβ binding was prevented and reversed by the well‐characterized orthosteric ligands of α7nAChR (epibatidine, α‐bungarotoxin, methylylcaconitine, PNU‐282987, S24795, and EVP6124) and by the type II positive allosteric modulator (PAM) PNU‐120596 but not by the type I PAM NS1738.Conclusions and ImplicationsOur TR‐FRET Aβ binding assay demonstrates for the first time the specific binding of Aβ to α7nAChR, which will be a crucial tool for the development, testing, and selection of a novel generation of AD drug candidates targeting Aβ/α7nAChR complexes with high specificity and fewer side effects compared to currently approved α7nAChR drugs.Linked ArticlesThis article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc
A photoswitchable GABA receptor channel blocker
Authors: Maleeva Galyna , Wutz Daniel , Rustler Karin , Nin‐Hill Alba , Rovira Carme , Petukhova Elena , Bautista‐Barrufet Antoni , Gomila‐Juaneda Alexandre , Scholze Petra , Peiretti Franck , Alfonso‐Prieto Mercedes , König Burkhard , Gorostiza Pau , Bregestovski Piotr 
Published: April 2019

Background and PurposeAnion‐selective Cys‐loop receptors (GABA and glycine receptors) provide the main inhibitory drive in the CNS. Both types of receptor operate via chloride‐selective ion channels, though with different kinetics, pharmacological profiles, and localization. Disequilibrium in their function leads to a variety of disorders, which are often treated with allosteric modulators. The few available GABA and glycine receptor channel blockers effectively suppress inhibitory currents in neurons, but their systemic administration is highly toxic. With the aim of developing an efficient light‐controllable modulator of GABA receptors, we constructed azobenzene‐nitrazepam (Azo‐NZ1), which is composed of a nitrazepam moiety merged to an azobenzene photoisomerizable group.Experimental ApproachThe experiments were carried out on cultured cells expressing Cys‐loop receptors of known subunit composition and in brain slices using patch‐clamp. Site‐directed mutagenesis and molecular modelling approaches were applied to evaluate the mechanism of action of Azo‐NZ1.Key ResultsAt visible light, being in trans‐configuration, Azo‐NZ1 blocked heteromeric α1/β2/γ2 GABAA receptors, ρ2 GABAA (GABAC), and α2 glycine receptors, whereas switching the compound into cis‐state by UV illumination restored the activity. Azo‐NZ1 successfully photomodulated GABAergic currents recorded from dentate gyrus neurons. We demonstrated that in trans‐configuration, Azo‐NZ1 blocks the Cl‐selective ion pore of GABA receptors interacting mainly with the 2′ level of the TM2 region.Conclusions and ImplicationsAzo‐NZ1 is a soluble light‐driven Cl‐channel blocker, which allows photo‐modulation of the activity induced by anion‐selective Cys‐loop receptors. Azo‐NZ1 is able to control GABAergic postsynaptic currents and provides new opportunities to study inhibitory neurotransmission using patterned illumination.
Age, stratigraphy, sedimentology and tectonic setting of the Sigri Pyroclastic Formation and its fossil forests, Early Miocene, Lesbos, Greece
Authors: Pe‐Piper Georgia , Piper David J.W. , Zouros Nickolas , Anastasakis George 
Published: April 2019

AbstractThe Petrified Forest of Lesbos comprises silicified tree fossils at multiple stratigraphic levels within the Lower Miocene Sigri Pyroclastic Formation. Our objective was to understand the interplay of tectonic setting, structural evolution, volcanological setting and basin evolution in the preservation of this remarkable natural monument. Sections were logged for lithology, sedimentary structures and hydrothermal alteration. Orientations of fallen fossil trees were measured. Samples were taken for mineralogical and geochemical analysis. 40Ar/39Ar dating was carried out on mineral separates from four samples. Widespread andesite‐dacite domes, the Eressos Formation, intrude and overlie metamorphic basement and are overlain by the Sigri Pyroclastic Formation, which comprises several hundreds of metres of pyroclastic flow tuffs (unwelded ignimbrites) interbedded with fluvial conglomerate and volcaniclastic sandstone. The Sigri Pyroclastic Formation ranges in age from 21.5 to 22 Ma, where it overlies the lacustrine Gavathas Formation, to younger than 18.4 Ma. Tuffs and fluvial conglomerates in the Sigri Pyroclastic Formation coarsen eastwards, and petrified trees and soil horizons occur throughout the Formation. The recurrence of pyroclastic flows was approximately one every 20 ka, so destructive flows were relatively infrequent, allowing the development of climax vegetation between most eruptions. Conglomerate‐filled channels show that rivers flowed westwards. Tree fall directions indicate NW to N movement of pyroclastic flows, implying a source near the younger Mesotopos–Tavari caldera to the south. The basin, which formed in a NNE‐trending dextral strike‐slip regime, provided some topographic steering. Following the Sigri Pyroclastic Formation at ca. 18 Ma, there was a rapid increase in the pace of volcanic activity, with the eruption of thick lava sequences and welded ignimbrites, and intrusion of dykes and laccoliths in SW Lesbos. Rapid burial by permeable tuffs, silica from alteration of volcanic ash, and later hydrothermal circulation all contributed to the preservation of the petrified trees.
Tumour necrosis factor alpha and interleukin‐5 inhibit olfactory regeneration via apoptosis of olfactory sphere cells in mice models of allergic rhinitis
Authors: Kim Dong‐Kyu , Choi Seung Ah , Eun Kyoung Mi , Kim Seung‐Ki , Kim Dae Woo , Phi Ji Hoon 
Published: April 2019

AbstractBackgroundOlfactory dysfunction is frequently experienced by patients with allergic rhinitis. It is thought to result from structural and functional changes occurring in the olfactory mucosa caused by inflammation. However, the current understanding of the pathophysiology of olfactory dysfunction in allergic rhinitis remains unclear.ObjectiveTo investigate the mechanism by which the olfactory neural cells are damaged in allergic rhinitis.MethodsOlfactory sphere cells (OSCs) were established after dissociation and serial cultures of cells from the mouse olfactory mucosa. Viability and proliferation of OSCs were compared between control and allergic rhinitis mice models, and olfactory stem cell markers were analysed in vivo. To elucidate which cytokines have an inhibitory effect on OSCs, viability and apoptotic markers of OSCs were investigated.ResultsOlfactory sphere cells were successfully isolated from the olfactory mucosa of mice, and these cells expressed markers of neural stem cells. To investigate the neural differentiation, we performed the immunocytochemical staining and found significantly elevated expressions of Tuji1, GFAP and O4 on OSCs. On the comparison of the characteristics of OSCs between control and allergic rhinitis model, we detected significantly fewer neurospheres, reduced clonogenic capacity and decreased expression of olfactory neural stem cell markers in allergic rhinitis model. When OSCs were treated with several major allergic cytokines were treated on OSCs, only TNF‐α showed an inhibitory effect on OSCs. Interestingly, IL‐5 had an inhibitory effect on the viability of OSCs in combination with TNF‐α, whereas IL‐5 alone does not have an effect. Moreover, TNF‐α combined with IL‐5 significantly increased the apoptotic expression, compared with TNF‐α or IL‐5 alone. Additionally, allergic rhinitis mice models showed the increased apoptotic expression.Conclusion and Clinical RelevanceAllergic rhinitis mice models showed lower expression of OSCs, and TNF‐α combined with IL‐5 had an apoptotic effect on OSCs. Therefore, these cytokines may be therapeutic targets for olfactory dysfunction in patients with allergic rhinitis.
Clinical characteristics and leptomeningeal collateral status in pediatric and adult patients with ischemic moyamoya disease
Authors: Liu Zhi‐Wen , Han Cong , Wang Hui , Zhang Qian , Li Si‐Jie , Bao Xiang‐yang , Zhang Zheng‐Shan , Duan Lian 
Published: April 2019

SummaryAimPrevious studies have found significant differences in clinical characteristics between pediatric and adult moyamoya disease (MMD) patients, but few studies have focused on the factors underlying these differences. We aimed to investigate the differences in leptomeningeal collateral (LMC) status between pediatric and adult MMD patients and to analyze the effects of LMCs on clinical characteristics and therapeutic prognosis.MethodsWe retrospectively analyzed 214 MMD patients from January 2014 to January 2016. Clinical characteristics and LMC status were compared between the pediatric and adult patients. LMC status was graded as good or poor depending on the retrograde flow from the posterior cerebral artery (PCA) on digital subtraction angiography (DSA).ResultsA total of 83 pediatric and 131 adult (1:1.6) MMD patients were analyzed. Pediatric patients were more likely to experience a transient ischemic attack (81%), whereas adult patients were more likely to experience infarction (51%). Regarding the different MMD stages (the early, medium, and advanced stages corresponded to Suzuki stages 1‐2, 3‐4, and 5‐6, respectively), the prevalence of good LMC status was higher for pediatric patients than for adult patients in the early stage (P = 0.047) and the medium stage (P = 0.001), but there were no differences between these patient groups in the advanced stage (P = 0.547). Worse postoperative angiographic outcomes (P = 0.017) were found in adult patients than in pediatric patients in the medium stage. Poor LMC status had strong correlations with infarction (P < 0.001 and P = 0.017) and poor postoperative outcomes (P = 0.003 and P = 0.043) in both pediatric and adult patients.ConclusionsPediatric MMD patients have greater patency and a greater ability to establish good LMC status than adult patients, and poor LMC status has a strong correlation with severe clinical symptoms and poor postoperative outcomes. LMC status may be an important factor in the differences in clinical characteristics and prognosis between pediatric and adult MMD patients.