bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of In Situ High-Fidelity Simulation Training on the Emergency management of Pneumonia (INSTEP): a mixed-methods study
Authors: Leng Owain Michael , Rothwell Charlotte , Buckton Annamarie , Elmer Catherine , Illing Jan , Metcalf Jane 
Published: March 2018

BackgroundThe patient safety agenda has propelled the rise of simulation education, but relatively few evaluations of simulation-based educational interventions have focused on patient outcomes.ObjectiveTo evaluate the impact of an in situ, high-fidelity simulation teaching intervention on the management of community-acquired pneumonia in the ambulatory care unit of a district general hospital.MethodsThis study used a mixed-methods approach to evaluate the impact of a programme of 10 in situ high-fidelity simulation education sessions delivered to a total of 10 junior doctors, nine nurses and seven healthcare assistants. Participants were tasked with managing a manikin simulating a patient with pneumonia in real time in a working clinical area. Subsequent structured debrief emphasised key themes from the national guidelines on pneumonia management. The intervention was evaluated through an immediate feedback form, follow-up semistructured interviews by independent qualitative researchers that underwent content analysis and triangulation with audit data on compliance with national pneumonia guidelines before and after the simulation intervention.ResultsThe in situ simulation intervention was valued by participants both in immediate written feedback and in follow-up semistructured interviews. In these interviews, 17 of 18 participants were able to identify a self-reported change in practice following the simulation intervention. Furthermore, most participants reported observing a change in the clinical practice of their colleagues following the training. Collected audit data did not show a statistically significant change in compliance with the guidelines for the management of pneumonia.ConclusionThis study found evidence of a change in both self-reported and observed clinical practice following a simulation intervention, supporting expert opinion that simulation education can impact clinician behaviours and patient outcomes in complex clinical scenarios. Furthermore, this feasibility study provides a transferrable method to evaluate the real-world impact of simulation education that merits further investigation through an appropriately powered study.
Legal status and malpractice
Authors: Coghlan Simon 
Published: March 2018

THIS series gives readers the opportunity to consider and contribute to discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved.In addition, a possible way forward is suggested; however, there is rarely a cut‐anddried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, ‘Legal status and malpractice’, was submitted and is discussed by Simon Coghlan. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue.The series is being coordinated by Dr Steven McCulloch, acting director of the Centre for Animal Welfare, University of Winchester. It aims to provide a framework that will help practising veterinarians find solutions when facing similar dilemmas.
Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes
Authors: Basha Mirta , Demeer Bénédicte , Revencu Nicole , Helaers Raphael , Theys Stephanie , Bou Saba Sami , Boute Odile , Devauchelle Bernard , Francois Geneviève , Bayet Bénédicte , Vikkula Miikka 
Published: March 2018

BackgroundOral clefts, that is, clefts of the lip and/or cleft palate (CL/P), are the most common craniofacial birth defects with an approximate incidence of ~1/700. To date, physicians stratify patients with oral clefts into either syndromic CL/P (syCL/P) or non-syndromic CL/P (nsCL/P) depending on whether the CL/P is associated with another anomaly or not. In general, patients with syCL/P follow Mendelian inheritance, while those with nsCL/P have a complex aetiology and, as such, do not adhere to Mendelian inheritance. Genome-wide association studies have identified approximately 30 risk loci for nsCL/P, which could explain a small fraction of heritability.MethodsTo identify variants causing nsCL/P, we conducted whole exome sequencing on 84 individuals with nsCL/P, drawn from multiplex families (n=46).ResultsWe identified rare damaging variants in four genes known to be mutated in syCL/P: TP63 (one family), TBX1 (one family), LRP6 (one family) and GRHL3 (two families), and clinical reassessment confirmed the isolated nature of their CL/P.ConclusionThese data demonstrate that patients with CL/P without cardinal signs of a syndrome may still carry a mutation in a gene linked to syCL/P. Rare coding and non-coding variants in syCL/P genes could in part explain the controversial question of ‘missing heritability’ for nsCL/P. Therefore, gene panels designed for diagnostic testing of syCL/P should be used for patients with nsCL/P, especially when there is at least third-degree family history. This would allow a more precise management, follow-up and genetic counselling. Moreover, stratified cohorts would allow hunting for genetic modifiers.
Magnetoelectric properties of Co-doped BiFeO3 nanoparticles
Authors: Shrimali V. G. , Rathod K. N. , Dhruv Davit , Zankat Alpa , Sagapariya Khushal , Solanki Sapana , Solanki P. S. , Shah N. A. , Kataria B. R. 
Published: March 2018

The magnetoelectric (ME) properties of sol–gel grown BiFe[Formula: see text]Co[Formula: see text]O3 (BFCO) nanoceramics, with different sizes, were investigated at room-temperature. X-ray diffraction (XRD) measurement was performed to investigate structural properties of the samples understudy. Magnetic field-dependent dielectric permittivity has been systematically investigated in the frequency range of 20 Hz to 1 MHz. To ensure the origin of magnetodielectric response, the magnetoimpedance (MI) spectroscopy was adopted using equivalent circuit model. The a.c. conductivity was found to obey the Jonscher’s universal power law. The modifications in spiral spin structure in the BFCO nanoparticles with size less than [Formula: see text]62 nm significantly affect the ME coupling parameters.
Depositional model for the distal Ordovician glaciated margin of Jordan; implications for the reservoir potential of the Risha Formation
Authors: Hirst J. Philip P. , Khatatneh Maher 
Published: March 2018

Abstract
Latest Ordovician glacial sediments crop out in southern Jordan and adjacent areas of Saudi Arabia, where they consist of mainly coarse clastics. These sediments were in part deposited within steep-sided tunnel valleys with palaeotransport towards the north to NE. In NE Jordan, the distal equivalents of some of these valley-confined clastics are encountered in the subsurface, where they form the reservoir units within the Risha gas field. Here, the succession consists of stacked sandstone units ranging from a few metres to >20 m thick alternating with thinner mudstone horizons. Some of the sandstone intervals show cleaning-upwards profiles and they can be correlated over tens of kilometres between the wells. Their lateral extents are much greater than the tunnel valleys and they are interpreted as stacked proglacial outwash sheets deposited subaqueously in front of the ice sheet. The reservoir quality of the sandstones has been compromised by extensive quartz cementation, although better porosities and permeabilities are preserved in the upper parts of some of the cleaning-upwards profiles, resulting in correlatable intervals from which gas is produced without stimulation.
Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness
Authors: Knutsen Russell H. , Beeman Scott C. , Broekelmann Thomas J. , Liu Delong , Tsang Kit Man , Kovacs Attila , Ye Li , Danback Joshua R. , Watson Anderson , Wardlaw Amanda , Wagenseil Jessica E. , Garbow Joel R. , Shoykhet Michael , Kozel Beth A. 
Published: March 2018

Increased vascular stiffness correlates with a higher risk of cardiovascular complications in aging adults. Elastin (ELN) insufficiency, as observed in patients with Williams-Beuren syndrome or with familial supravalvular aortic stenosis, also increases vascular stiffness and leads to arterial narrowing. We used Eln+/− mice to test the hypothesis that pathologically increased vascular stiffness with concomitant arterial narrowing leads to decreased blood flow to end organs such as the brain. We also hypothesized that drugs that remodel arteries and increase lumen diameter would improve flow. To test these hypotheses, we compared carotid blood flow using ultrasound and cerebral blood flow using MRI-based arterial spin labeling in wild-type (WT) and Eln+/− mice. We then studied how minoxidil, an ATP-sensitive K+ channel opener and vasodilator, affects vessel mechanics, blood flow, and gene expression. Both carotid and cerebral blood flows were lower in Eln+/− mice than in WT mice. Treatment of Eln+/− mice with minoxidil lowered blood pressure and reduced functional arterial stiffness to WT levels. Minoxidil also improved arterial diameter and restored carotid and cerebral blood flows in Eln+/− mice. The beneficial effects persisted for weeks after drug removal. RNA-Seq analysis revealed differential expression of 127 extracellular matrix-related genes among the treatment groups. These results indicate that ELN insufficiency impairs end-organ perfusion, which may contribute to the increased cardiovascular risk. Minoxidil, despite lowering blood pressure, improves end-organ perfusion. Changes in matrix gene expression and persistence of treatment effects after drug withdrawal suggest arterial remodeling. Such remodeling may benefit patients with genetic or age-dependent ELN insufficiency. NEW & NOTEWORTHY Our work with a model of chronic vascular stiffness, the elastin ( Eln)+/− mouse, shows reduced brain perfusion as measured by carotid ultrasound and MRI arterial spin labeling. Vessel caliber, functional stiffness, and blood flow improved with minoxidil. The ATP-sensitive K+ channel opener increased Eln gene expression and altered 126 other matrix-associated genes.
Overall and Visceral Adiposity Are Associated with Incident Cardiovascular Disease among Breast Cancer Patients: Results from the B-SCANS Study
Authors: Cespedes Feliciano EM , WY Chen , Kroenke CH , Bradshaw PT , Alexeeff S , Caan BJ 
Published: March 2018

Abstract
It is assumed that total and visceral adiposity increase cardiovascular disease (CVD) risk among breast cancer survivors; yet, these associations have not been studied, and could differ from non-cancer populations due to the modifying effects of cancer treatment. METHODS: We studied 2,630 Stage I–III breast cancer patients without pre-existing CVD diagnosed at Kaiser Permanente (2006–2013). We quantified body composition from computed tomography scans taken at breast cancer diagnosis. The main exposures were total and visceral adiposity indices (cm2/m2), examined in tertiles. From ICD codes, we identified non-fatal stroke, coronary artery disease (CAD), and heart failure, and a composite outcome including CVD death (CVD). We estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusting for age, smoking, tumor (stage, grade, and ER/PR and HER2 status) and treatment (chemotherapy and/or radiation) factors, skeletal muscle index (SMI), and body mass index (BMI) residuals. We assessed effect modification via product terms of adiposity with age (&gt;=/&lt;55 years), sarcopenia (SMI&gt;=/&lt;40 cm2/m2) and chemotherapy (yes/no). RESULTS: At diagnosis, mean (SD) age was 55 (11) years and BMI was 28 (6) kg/m2. Over a maximum follow-up of 11 years, 669 CVD events occurred. Independent of BMI and other covariates, women in the highest (v. lowest) tertile of total adiposity had a higher risk of CVD, heart failure, stroke and CAD; HRs (95%CI) were 1.45 (1.15–1.81), 1.78 (1.24–2.57), 1.89 (1.25–2.87), and 1.52 (0.83–2.79), respectively. Results were similar for visceral adiposity, and by age and sarcopenia, but were stronger for women receiving chemotherapy: e.g., the HR (95%CI) for the highest (v. lowest) tertile of total adiposity with CVD risk was 1.76 (1.33–2.33) for women who received chemotherapy versus 0.93 (0.63–1.38) for women who did not, p- interaction = 0.04. CONCLUSIONS: Women who enter a breast cancer diagnosis with greater total and visceral adiposity are at higher risk of subsequent CVD, particularly if they receive chemotherapy. Our results suggest that body composition - independent of BMI and other factors - can identify patients with high CVD risk for additional monitoring, tailored treatment plans and targeting of preventive interventions.
Breast Density and Risk of Invasive Breast Cancer among Older Women Undergoing Mammography: The Breast Cancer Surveillance Consortium Cohort Study
Authors: Braithwaite D , Miglioretti DL , Zhu W , Demb J , Trentham-Dietz A , Sprague B , Tice JA , Onega T , Henderson LM , Buist DSM , Walter LC , Kerlikowske K 
Published: March 2018

Abstract
This study examined whether breast density is associated with risk of breast cancer in women age ≥65 years undergoing screening mammography in community practice. Methods: We used prospective cohort data between 1996 and 2012 from the Breast Cancer Surveillance Consortium (BCSC). We calculated separate cumulative incidence models for breast cancer incidence according to Breast Imaging Reporting and Data System (BI-RADS) breast density for women ages 65–74 and ages ≥75. Multivariable Cox proportional hazards regression models were fitted to determine the risk of invasive breast cancer adjusted for BCSC registry, race/ethnicity, BMI, hormone therapy use and benign breast disease. Results: Among the 403,268 women included in the study, approximately 40% were ages ≥75. The annual incidence rate of invasive breast cancer increased with increasing breast density among women ages 65–74 [BI- RADS fatty breasts: 2.2% (95% CI, 2.1%–2.4%) vs. heterogeneously or extremely dense breasts: 4.7% (95% CI, 4.6%–4.9%)] and women ages 75+ [BI-RADS fatty breasts: 2.3% (95% CI, 2.1%–2.5%) vs. heterogeneously or extremely dense: 4.3% (95% CI, 4.1%–4.5%)]. Women with BI-RADS fatty breasts had a decreased risk of breast cancer among women ages 65–74 [HR: 0.66 (95% CI: 0.58%–0.78%) and women ages ≥75 [HR: 0.73 (95% CI: 0.62%–0.87%). Women with BI-RADS heterogeneously or extremely dense breasts were found to have increased risk of breast cancer among women ages 65–74 [HR: 1.39 (95% CI: 1.28%–1.51%)] and women ages ≥75 [HR: 1.23 (95% CI: 1.10%–1.37%)]. Conclusions: Older women with higher BI-RADS density had a significantly increased risk of breast cancer. These findings add further evidence that breast density continues to be associated with an increased risk of breast cancer, even among women age ≥75 years.
Clinical and Psychological Predictors of Switching from Active Surveillance to Active Treatment among Men with Low-Risk Prostate Cancer: the PREPARE Prospective Cohort Study
Authors: Taylor KL , Luta G , Zotou V , Hoffman RM , Lobo T , Davis KM , Potosky AL , Aaronson D , Van Den Eeden S 
Published: March 2018

Abstract
Numerous observational studies have assessed the clinical predictors of switching from active surveillance (AS) to active treatment (AT), but few have assessed psychological and decisional predictors. In a prospective, comparative effectiveness cohort study of men newly diagnosed with low-risk PCa, we assessed whether psychological and decisional factors predicted switching to AT after adjusting for clinical factors. We conducted pre-treatment telephone interviews (N = 1,139; 69.3% participation) with low-risk PCa patients (PSA &lt; 10, Gleason &lt; 7) and a follow-up assessment 6–10 months post-diagnosis (N = 1057; 93%). Clinical variables were obtained from the medical record. The current analysis included men who were on AS for up to 24 months (N = 515), compared to men on AS for &gt;12 months who switched to AT between 12–24 months (N = 86). In Cox proportional hazard models, we included 2 time-dependent covariates measured between diagnosis and 24-months post-diagnosis: PSA (&lt;4, 4–9.99, 10+) and Gleason score (&lt;7, 7+, no surveillance biopsy). Baseline covariates included age (X = 62.3 (SD = 7.0), first degree relative with PCa (25%), number of positive cores (&lt;2 = 75%), urologist initial treatment recommendation (14% AT). Covariates measured at 6 months included prostate- specific anxiety, decisional satisfaction, decisional uncertainty, and preference for shared vs. independent decisions. The fully adjusted model indicated that switching to an active treatment was more likely among those with a PSA &gt; 10 (HR 5.6, 2.4–13.1), Gleason 7+ (HR 20.2, 12.2–33.4), and the urologist's initial recommendation of AT (HR 2.1, 1.04–4.2). The psychological variables, including preference for making independent treatment decisions (HR 2.7, 1.07–6.9) and concern that disease progression will not be detected (HR 1.5, 0.95–2.4), were independently associated with undergoing AT. After adjusting for clinical evidence of disease progression over the first two years post-diagnosis, men's concerns that disease progression will not be detected and preference for making their own treatment decision each independently predicted undergoing AT. These findings suggest the need to provide information and assistance to men who may be uncertain about remaining on AS, particularly when AS remains clinically indicated.
Cumulative Incidence of Non-breast Cancer Mortality and Breast Cancer Risk by Comorbidity and Age among Older Women Undergoing Screening Mammography: The Medicare-linked Breast Cancer Surveillance Consortium Cohort Study
Authors: Demb J , Abraham L , Miglioretti DL , Buist DSM , Sprague B , Walter LC , O'Meara ES , Schousboe J , Henderson LM , Kerlikowske K , Braithwaite D 
Published: March 2018

Abstract
Due to an increasing comorbidity burden with aging, the margin of benefit from screening mammography in women ages ≥65 is highly variable. This study examined 10-year cumulative risk of non-breast cancer mortality and breast cancer by comorbidity and age in a screening population. Methods: We used prospective cohort data from the Breast Cancer Surveillance Consortium (BCSC), which included 198,362 women ages ≥65 years who have undergone at least one screening mammogram. We calculated cumulative incidence of non-breast cancer mortality and risk of breast cancer 10 years following the screening mammogram for women ages 65–74, 75–84 and ≥85 years stratified by the Charlson Comorbidity Index (CCI scores 0, 1 and ≥2). Results: During a median follow-up time of 8.1 years (interquartile range, 4.6 to 10 years), 34,768 died from non-breast cancer causes and 6,327 women were diagnosed with invasive breast cancer of whom 359 died from breast cancer and 942 from non-breast cancer causes. The 10-year cumulative risk of invasive breast cancer following a screening mammogram did not significantly decrease with elevating CCI score and age for women ages 65–74 [CCI 0 = 4.0% (95% CI, 3.9%–4.1%) vs. CCI ≥2 = 3.8% (95% CI, 3.3%–4.3%)], ages 75–84 [CCI 0 = 3.7% (95% CI, 3.5%–3.9%) vs. CCI ≥ 2 = 3.4% (95% CI, 2.8%–4.0%)], and ages ≥85 [CCI 0 = 2.7%, (95% CI, 2.3%–3.2%) vs. CCI ≥ 2 = 2.5% (95% CI, 1.4%–3.6%)]. Cumulative risk of non-breast cancer mortality significantly increased with increasing CCI and age for women ages 65–74 [CCI 0 = 11% (95% CI, 10%–11%] vs. CCI ≥ 2 = 45% (95% CI, [43%–46%)], ages 75–84 [CCI 0 = 29% (95% CI, 29%–30%) vs. CCI ≥2 = 62% (95% CI, 60%–63%)], and ages ≥85 [CCI 0 = 59%, (95% CI, 57%–60%) vs. CCI ≥2 = 84% (95% CI, 81%–86%)]. Conclusion: Risk of non-breast cancer mortality was high and significantly increased with rising comorbidity burden and age whereas breast cancer risk was low and non-significantly decreased with both. These results suggest that women with a CCI score of ≥2 or ages ≥75 years may experience minimal benefit from continuing routine screening mammography. Future research is needed to delineate the specific benefits and harms of screening mammography in subsets of older women defined by age and comorbidity burden.
In Vivo E2F Reporting Reveals Efficacious Schedules of MEK1/2–CDK4/6 Targeting and mTOR–S6 Resistance Mechanisms
Authors: Teh Jessica L.F. , Cheng Phil F. , Purwin Timothy J. , Nikbakht Neda , Patel Prem , Chervoneva Inna , Ertel Adam , Fortina Paolo M. , Kleiber Ines , HooKim Kim , Davies Michael A. , Kwong Lawrence N. , Levesque Mitch P. , Dummer Reinhard , Aplin Andrew E. 
Published: March 2018

Abstract
Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance.
Significance: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens. Cancer Discov; 8(5); 568–81. ©2018 AACR.
See related commentary by Sullivan, p. 532.
See related article by Romano et al., p. 556.
This article is highlighted in the In This Issue feature, p. 517
Digital Circulating Tumor Cell Analyses for Prostate Cancer Precision Oncology
Authors: Heitzer Ellen , Speicher Michael R. 
Published: March 2018

Abstract
Summary: In this issue of Cancer Discovery, Miyamoto and colleagues adapted their microfluidic CTC-iChip isolation platform with a digital RNA-PCR readout for eight prostate-specific transcripts and two assays for the androgen receptor mRNA splice variant ARV7 and the TMPRSS2–ERG translocation transcript. In patients with metastatic castrate-resistant prostate cancer at initiating abiraterone therapy in a first-line setting, the resulting RNA-based digital circulating tumor cell signatures identified patients with a shorter overall survival, and in patients with clinically localized disease, the signatures identified those with seminal vesicle invasion and pelvic lymph node involvement. Cancer Discov; 8(3); 269–71. ©2018 AACR.
See related article by Miyamoto et al., p. 288.
Driver Oncogenes but Not as We Know Them: Targetable Fusion Genes in Breast Cancer
Authors: Natrajan Rachael , Tutt Andrew N.J. , Lord Christopher J. 
Published: March 2018

Abstract
Summary: Two reports in this issue of Cancer Discovery outline how the genomic composition of tumors, including the presence of intragenic gene fusions, could inform the selection of treatment approaches in aggressive forms of the disease. Cancer Discov; 8(3); 272–5. ©2018 AACR.
See related article by Matissek et al., p. 336.
See related article by Liu et al., p. 354.