bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of a complex intervention on Prioritising Multimedication in Multimorbidity (PRIMUM) in primary care: results of a pragmatic cluster randomised controlled trial
Authors: Muth Christiane , Uhlmann Lorenz , Haefeli Walter E , Rochon Justine , van den Akker Marjan , Perera Rafael , Güthlin Corina , Beyer Martin , Oswald Frank , Valderas Jose Maria , Knottnerus J André , Gerlach Ferdinand M , Harder Sebastian 
Published: September 2019

ObjectivesInvestigate the effectiveness of a complex intervention aimed at improving the appropriateness of medication in older patients with multimorbidity in general practice.DesignPragmatic, cluster randomised controlled trial with general practice as unit of randomisation.Setting72 general practices in Hesse, Germany.Participants505 randomly sampled, cognitively intact patients (≥60 years, ≥3 chronic conditions under pharmacological treatment, ≥5 long-term drug prescriptions with systemic effects); 465 patients and 71 practices completed the study.InterventionsIntervention group (IG): The healthcare assistant conducted a checklist-based interview with patients on medication-related problems and reconciled their medications. Assisted by a computerised decision support system, the general practitioner optimised medication, discussed it with patients and adjusted it accordingly. The control group (CG) continued with usual care.Outcome measuresThe primary outcome was a modified Medication Appropriateness Index (MAI, excluding item 10 on cost-effectiveness), assessed in blinded medication reviews and calculated as the difference between baseline and after 6 months; secondary outcomes after 6 and 9 months’ follow-up: quality of life, functioning, medication adherence, and so on.ResultsAt baseline, a high proportion of patients had appropriate to mildly inappropriate prescriptions (MAI 0–5 points: n=350 patients). Randomisation revealed balanced groups (IG: 36 practices/252 patients; CG: 36/253). Intervention had no significant effect on primary outcome: mean MAI sum scores decreased by 0.3 points in IG and 0.8 points in CG, resulting in a non-significant adjusted mean difference of 0.7 (95% CI −0.2 to 1.6) points in favour of CG. Secondary outcomes showed non-significant changes (quality of life slightly improved in IG but continued to decline in CG) or remained stable (functioning, medication adherence).ConclusionsThe intervention had no significant effects. Many patients already received appropriate prescriptions and enjoyed good quality of life and functional status. We can therefore conclude that in our study, there was not enough scope for improvement.Trial registration numberISRCTN99526053.NCT01171339; Results.
Update of a clinical prediction model for serious bacterial infections in preschool children by adding a host-protein-based assay: a diagnostic study
Authors: van Houten Chantal , van de Maat Josephine Sophia , Naaktgeboren Christiana , Bont Louis , Oostenbrink R 
Published: September 2019

ObjectiveTo determine whether updating a diagnostic prediction model by adding a combination assay (tumour necrosis factor-related apoptosis-inducing ligand, interferon γ induced protein-10 and C reactive protein (CRP)) can accurately identify children with pneumonia or other serious bacterial infections (SBIs).DesignObservational double-blind diagnostic study.SettingTwo hospitals in Israel and four hospitals in the Netherlands.Patients591 children, aged 1–60 months, presenting with lower respiratory tract infections or fever without source. 96 of them had SBIs. The original Feverkidstool, a polytomous logistic regression model including clinical variables and CRP, was recalibrated and thereafter updated by using the assay.Main outcome measuresPneumonia, other SBIs or no SBI.ResultsThe recalibrated original Feverkidstool discriminated well between SBIs and viral infections, with a c-statistic for pneumonia of 0.84 (95% CI 0.77 to 0.92) and 0.82 (95% CI 0.77 to 0.86) for other SBIs. The discriminatory ability increased when CRP was replaced by the combination assay; c-statistic for pneumonia increased to 0.89 (95% CI 0.82 to 0.96) and for other SBIs to 0.91 (95% CI 0.87 to 0.94). This updated Feverkidstool improved diagnosis of SBIs mainly in children with low–moderate risk estimates of SBIs.ConclusionWe improved the diagnostic accuracy of the Feverkidstool by replacing CRP with a combination assay to predict pneumonia or other SBIs in febrile children. The updated Feverkidstool has the largest potential to rule out bacterial infections and thus to decrease unnecessary antibiotic prescription in children with low-to-moderate predicted risk of SBIs.
Assessing competency using simulation: the SimZones approach
Authors: Roussin Christopher , Sawyer Taylor , Weinstock Peter 
Published: September 2019

IntroductionCompetency-based medical education (CBME) is a system of medical training that focuses on a structured approach to developing the clinical abilities of medical education graduates and practicing physicians. CBME requires a robust and multifaceted system of assessment in order to both measure and guide the progress of learners toward pre-established goals. Simulation has been proposed as one method for assessing competency in healthcare workers. However, a longitudinal framework for assessing competency using simulation has not been developed.MethodsConjecture mapping methodology was used to map Miller’s framework for competency assessment—‘knows’, ‘knows how’, ‘shows how’, and ‘does’—to the five SimZones described by Roussin and Weinstock. The SimZones describe a system of organising the development and delivery of simulation-based education and offer a foundation for both guiding and organising assessment in a simulation context.ResultsA conceptualised alignment of the SimZones with Miller’s pyramid of assessment was developed, as well as a detailed conjecture map. SimZone 0 (auto-feedback) and SimZone 1 (foundational instruction) mapped to ‘knows’ and ‘knows how’. SimZone 2 (acute care instruction) mapped to ‘shows how’. SimZone 3 (team and system development) mapped to ‘shows how’. SimZone 4 (real-life debriefing and development) mapped to ‘does’.ConclusionThe SimZones system of competency assessment offers a robust, flexible, and multifaceted system to guide both formative and summative assessment in CBME. The SimZones approach adds to the many methods of competency assessment available to educators. Adding SimZones to the vocabulary of CBME may be helpful for the full deployment of CBME.
Do age, period or cohort effects explain circulatory disease mortality trends, Scotland 1974–2015?
Authors: Parkinson Jane , Minton Jon , Bouttell Janet , Lewsey James , Shah Anoop , McCartney Gerry 
Published: September 2019

ObjectiveWe aimed to explore whether age, period or cohort effects explain the trends and inequalities in ischaemic heart disease (IHD) and cerebrovascular disease (CeVD) mortality in Scotland.MethodsWe analysed IHD and CeVD deaths for 1974–2015 by sex, age and area deprivation, visually explored the data using heatmaps and dotplots and built regression models.ResultsCeVD mortality improved steadily over time while IHD mortality improved more rapidly from the late 1980s. Age effects were evident; both outcomes showed an exponential relationship with age for all except males for IHD in the 1980s and 1990s. The mortality profiles by age became older, although improvement was slower for those aged <50 years for IHD, especially for males, and faster for CeVD in females aged <65 years. Rates were higher, and inequalities greater, among males, especially for IHD. For IHD, increased risk for males over females reduced with age (incidence rate ratio for 41–50 year old males=4.28 (95% CI 4.12 to 4.44) and 1.17 (95% CI 1.16 to 1.18) for 71–80 year olds). Inequalities in IHD mortality by area deprivation persisted over time, increasing from around 10% to around 25% higher risk in the most deprived areas between 1974 and 1986 before declining in absolute terms from around 2000. Inequalities for CeVD increased after the late 1980s.ConclusionsIHD and CeVD mortality in Scotland exhibit age but not recent distinct period or cohort effects. The improvements in mortality rates have been more sustained for CeVD and inequalities greater for IHD.
Ethanolic extract and ethyl acetate fraction of Coutoubea spicata attenuate hyperglycemia, oxidative stress, and muscle damage in alloxan-induced diabetic rats subjected to resistance exercise training program
Authors: Santos Jymmys Lopes dos , Araújo Silvan Silva de , Silva Ana Mara de Oliveira e , Lima Clésio Andrade , Vieira Souza Lúcio Marques , Costa Rôas Araújo , Aidar Martins Felipe José , Voltarelli Fabrício Azevedo , Estevam Charles dos Santos , Marçal Anderson Carlos 
Published: September 2019

Gentianaceae family (such as Coutoubea spicata) contains iridoids and flavonoids with antidiabetic properties. However, there is no information available about the antidiabetic effects of C. spicata when combined with resistance exercise training (RET). This study evaluated the effects of the ethanolic extract (EE) and ethyl acetate fraction (EAF) of C. spicata on biochemical markers, muscle damage, and oxidative stress in diabetic rats submitted to RET. Alloxan-induced diabetic rats were distributed into 4 groups (each group, n = 8) treated with distilled water (TD), EE, EAF, or metformin and submitted to RET. Two groups without the disease (each group, n = 8) (sedentary control and trained control), as well as a sedentary diabetic group (n = 8) were included. Body weight and glycemia were evaluated weekly. After 30 days, lipid/lipoprotein profile, aspartate aminotransferase, alanine aminotransferase, muscle damage ((creatine kinase (CK) and lactate dehydrogenase (LDH)), and oxidative stress (malondialdehyde (MDA), sulfhydryl groups (SH), and ferric reducing antioxidant power) were evaluated. MDA and SH for pancreas, liver, heart, and muscle were evaluated. C. spicata extract and fraction combined with RET recovered body weight and reduced glycemia, muscle damage (CK: 36.83% and 21.45%; LDH: 49.83% and 68.55%), and low-density lipoprotein cholesterol (70.63%; 59.18%) and improved redox status (MDA: 50.33%, 39.74%; and SH: 53.97%; 76.41%), respectively, when compared with the TD group. C. spicata plus RET promoted anti-hyperglycemic, lipid-reducing, and antioxidant effects in diabetic rats. Novelty C. spicata presents anti-hyperglycemic and lipid-lowering effects potentiated by RET. C. spicata reduces muscle injury and increases antioxidant defense.
Analysis of the X(3842) as a D-wave charmonium meson
Authors: Yu Guo-Liang , Wang Zhi-Gang 
Published: September 2019

In this paper, we assign the newly reported state [Formula: see text] to be a [Formula: see text]-wave [Formula: see text] meson, and study its mass and decay constant with QCD sum rules by considering the contributions of vacuum condensates up to dimension-6 in the operator product expansion. The predicted mass [Formula: see text] GeV is in agreement with the experimental data [Formula: see text] MeV from the LHCb collaboration. This result supports assigning [Formula: see text] as the [Formula: see text] charmonium meson. In this case, its predicted strong decay width with the [Formula: see text] decay model is compatible with the experimental data.
On the importance of the nonuniform aortic stiffening in the hemodynamics of physiological aging
Authors: Pagoulatou Stamatia Z. , Bikia Vasiliki , Trachet Bram , Papaioannou Theodore G. , Protogerou Athanase D. , Stergiopulos Nikolaos 
Published: September 2019

Mathematical models of the arterial tree constitute a valuable tool to investigate the hemodynamics of aging and pathology. Rendering such models as patient specific could allow for the assessment of central hemodynamic variables of clinical interest. However, this task is challenging, particularly with respect to the tuning of the local area compliance that varies significantly along the arterial tree. Accordingly, in this study, we demonstrate the importance of taking into account the differential effects of aging on the stiffness of central and peripheral arteries when simulating a person’s hemodynamic profile. More specifically, we propose a simple method for effectively adapting the properties of a generic one-dimensional model of the arterial tree based on the subject’s age and noninvasive measurements of aortic flow and brachial pressure. A key element for the success of the method is the implementation of different mechanisms of arterial stiffening for young and old individuals. The designed methodology was tested and validated against in vivo data from a population of n = 20 adults. Carotid-to-femoral pulse wave velocity was accurately predicted by the model (mean error = 0.14 m/s, SD = 0.77 m/s), with the greatest deviations being observed for older subjects. In regard to aortic pressure, model-derived systolic blood pressure and augmentation index were both in good agreement (mean difference of 2.3 mmHg and 4.25%, respectively) with the predictions of a widely used commercial device (Mobil-O-Graph). These preliminary results encourage us to further validate the method in larger samples and consider its potential as a noninvasive tool for hemodynamic monitoring. NEW & NOTEWORTHY We propose a technique for adapting the parameters of a validated one-dimensional model of the arterial tree using noninvasive measurements of aortic flow and brachial pressure. Emphasis is given on the adjustment of the arterial tree distensibility, which incorporates the nonuniform effects of aging on central and peripheral vessel elasticity. Our method could find application in the derivation of important hemodynamic indices, paving the way for novel diagnostic tools.
Mechanisms and Antitumor Activity of a Binary EGFR/DNA–Targeting Strategy Overcomes Resistance of Glioblastoma Stem Cells to Temozolomide
Authors: Sharifi Zeinab , Abdulkarim Bassam , Meehan Brian , Rak Janusz , Daniel Paul , Schmitt Julie , Lauzon Nidia , Eppert Kolja , Duncan Heather M. , Petrecca Kevin , Guiot Marie-Christine , Jean-Claude Bertrand , Sabri Siham 
Published: September 2019

Abstract

Purpose:
Glioblastoma (GBM) is a fatal primary malignant brain tumor. GBM stem cells (GSC) contribute to resistance to the DNA-damaging chemotherapy, temozolomide. The epidermal growth factor receptor (EGFR) displays genomic alterations enabling DNA repair mechanisms in half of GBMs. We aimed to investigate EGFR/DNA combi-targeting in GBM.

Experimental Design:
ZR2002 is a “combi-molecule” designed to inflict DNA damage through its chlorethyl moiety and induce irreversible EGFR tyrosine kinase inhibition. We assessed its in vitro efficacy in temozolomide-resistant patient-derived GSCs, mesenchymal temozolomide-sensitive and resistant in vivo–derived GSC sublines, and U87/EGFR isogenic cell lines stably expressing EGFR/wild-type or variant III (EGFRvIII). We evaluated its antitumor activity in mice harboring orthotopic EGFRvIII or mesenchymal TMZ-resistant GSC tumors.

Results:
ZR2002 induced submicromolar antiproliferative effects and inhibited neurosphere formation of all GSCs with marginal effects on normal human astrocytes. ZR2002 inhibited EGF-induced autophosphorylation of EGFR, downstream Erk1/2 phosphorylation, increased DNA strand breaks, and induced activation of wild-type p53; the latter was required for its cytotoxicity through p53-dependent mechanism. ZR2002 induced similar effects on U87/EGFR cell lines and its oral administration significantly increased survival in an orthotopic EGFRvIII mouse model. ZR2002 improved survival of mice harboring intracranial mesenchymal temozolomide-resistant GSC line, decreased EGFR, Erk1/2, and AKT phosphorylation and was detected in tumor brain tissue by MALDI imaging mass spectrometry.

Conclusions:
These findings provide the molecular basis of binary EGFR/DNA targeting and uncover the oral bioavailability, blood–brain barrier permeability, and antitumor activity of ZR2002 supporting potential evaluation of this first-in-class drug in recurrent GBM.
The Zinc-Finger AN1-Type Domain 2a Gene Acts as a Regulator of Cell Survival in Human Melanoma: Role of E3-Ligase cIAP2
Authors: Pizzato Scomazzon Sofia , Riccio Anna , Santopolo Silvia , Lanzilli Giulia , Coccia Marta , Rossi Antonio , Santoro M. Gabriella 
Published: September 2019

Abstract

The zinc-finger AN1-type domain-2a gene, also known as AIRAP (arsenite-inducible RNA-associated protein), was initially described as an arsenite-inducible gene in Caenorhabditis elegans and mammalian cells. Differently from the AIRAP worm homologue, aip-1, a gene known to play an important role in preserving animal lifespan and buffering arsenic-induced proteotoxicity, mammals have a second, constitutively expressed, AIRAP-like gene (AIRAPL), recently implicated in myeloid transformation. We have identified human AIRAP as a canonical heat-shock gene, whose expression, differently from AIRAPL, is strictly dependent on the proteotoxic-stress regulator heat-shock factor 1 (HSF1). AIRAP function is still not well defined and there is no information on AIRAP in cancer. Herein we show that bortezomib and next-generation proteasome inhibitors ixazomib and carfilzomib markedly induce AIRAP expression in human melanoma at concentrations comparable to plasma-levels in treated patients. AIRAP-downregulation leads to bortezomib sensitization, whereas AIRAP-overexpression protects melanoma cells from the drug, identifying AIRAP as a novel HSF1-regulated marker of chemotherapy resistance. More importantly, this study unexpectedly revealed that, also in the absence of drugs, AIRAP-silencing hinders melanoma clonogenic potential and spheroid growth, promoting caspase activation and apoptotic cell death, an effect independent of AIRAPL and linked to downregulation of the antiapoptotic protein cIAP2. Interestingly, AIRAP was found to interact with cIAP2, regulating its stability in melanoma. Taken together, the results identify AIRAP as a novel HSF1-dependent regulator of prosurvival networks in melanoma cells, opening new therapeutic perspectives in chemoresistant melanoma treatment.

Implications:
The findings identify ZFAND2A/AIRAP as a novel stress-regulated survival factor implicated in the stabilization of the antiapoptotic protein cIAP2 and as a new potential therapeutic target in melanoma.
Readmissions After Acute Myocardial Infarction: How Often Do Patients Return to the Discharging Hospital?
Authors: Rymer Jennifer A. , Chen Anita Y. , Thomas Laine , Fonarow Gregg C. , Peterson Eric D. , Wang Tracy Y. 
Published: September 2019

Background

When patients require readmission after a recent myocardial infarction (
MI
), returning to the discharging (index) hospital may be associated with better outcomes as a result of greater continuity in care. However, little evidence exists to answer this frequent patient question.

Methods and Results

Among Medicare patients aged ≥65 years discharged home alive post‐
MI
from 491
US
hospitals in the ACTION (Acute Coronary Treatment Intervention Outcomes Network) Registry, we compared reason for readmission, duration of rehospitalization, and 30‐day mortality between patients readmitted to the index versus nonindex hospital within 30 days of index
MI
discharge. Among 53 471
MI
patients, 7715 (14%) were readmitted within 30 days, and most readmitted patients (73%) returned to the discharging hospital. Reason for readmission was not significantly associated with location of readmission. In multivariable modeling, the strongest factors associated with readmission to a nonindex hospital were distance from the discharging hospital, transfer‐in during the index
MI
hospitalization, and frequency of nonindex hospital admissions in the year preceding to the index
MI
. Duration of rehospitalization did not differ significantly between patients readmitted to the index versus nonindex hospital (median, 4 versus 3 days;
P
=0.17). Mortality risk was also not significantly different between patients readmitted to the index versus nonindex hospital overall (7.4 versus 7.7%; adjusted odds ratio, 0.89; 95%
CI
, 0.73–1.10) and when stratified by reason for readmission (
P
for interaction=0.61).

Conclusions

Post‐
MI
readmissions did not differ in reason for readmission, duration of rehospitalization, or associated mortality when compared between patients who returned to the discharging hospital and those who sought care elsewhere.
Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction
Authors: Vorasayan Pongpat , Bevers Matthew B. , Beslow Lauren A. , Sze Gordon , Molyneaux Bradley J. , Hinson Holly E. , Simard J. Marc , von Kummer Rüdiger , Sheth Kevin N. , Kimberly W. Taylor 
Published: September 2019

Background and Purpose—
Prior studies have shown a linear relationship between computed tomography (CT)–derived radiodensity and water uptake, or brain edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke).

Methods—
This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU.

Results—

A median of 3 CT scans (interquartile range, 2–4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (β=0.23; 95% CI, 0.20–0.26;
P
<0.001). Treatment with intravenous glibenclamide was associated with reduced NWU (β=−2.80; 95% CI, −5.07 to −0.53;
P
=0.016) and reduced MLS (β=−1.50; 95% CI, −2.71 to −0.28;
P
=0.016). Treatment with intravenous glibenclamide reduced both gray and white matter water uptake. In mediation analysis, gray matter NWU (β=0.15; 95% CI, 0.11–0.20;
P
<0.001) contributed to a greater proportion of MLS mass effect, as compared with white matter NWU (β=0.08; 95% CI, 0.03–0.13;
P
=0.001).

Conclusions—
In this phase 2 post hoc analysis, intravenous glibenclamide reduced both water accumulation and mass effect after large hemispheric infarction. This study demonstrates NWU is a quantitative and modifiable biomarker of ischemic brain edema accumulation.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01794182.