bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of simulation methods for teaching peripheral arterial examination to medical students
Authors: Naqi Syed Ali , Salih Abdel Monim , Hoban Anthony , Ayoub Firas , Quirke Michael , Hill Arnold D K , Condron Claire 
Published: October 2017

Physical examination is a critical component of medical practice yet the focus on efficient patient turnover has impacted the availability of patients with clinical findings willing to be examined by students and skills' teaching is not consistent across clinical rotations. This work evaluates simulation methodologies for teaching of the peripheral arterial examination and evaluates whether skills learnt are transferable to clinical practice.Second-year medical students were taught peripheral arterial examination on a SimMan 3G or with simulated patients (SPs). Both groups were assessed by Objective Structured Clinical Examination (OSCE) with outpatients who have been diagnosed with peripheral arterial disease.There was no difference in the pass rate at OSCE between the two groups. SimMan better facilitated repeated practice, group learning, peer teaching and discussion, which were highly valued by the students. Students felt that the SImMan tutorial did not facilitate development of spatial cognition or pattern recognition. They also felt less well prepared to deal with real patients in terms of having practised appropriate language, issuing instructions and attempting to reassure patients.Both methods of simulation teaching have distinct merits and the ideal approach maybe to use the SimMan in combination with SPs.
Student-inflicted injuries to staff in schools: comparing risk between educators and non-educators
Authors: Schofield Katherine E , Ryan Andrew D , Stroinski Craig 
Published: October 2017

ObjectiveStudent-inflicted injury to staff in the educational services sector is a growing concern. Studies on violence have focused on teachers as victims, but less is known about injuries to other employee groups, particularly educational assistants. Inequities may be present, as educational assistants and non-educators may not have the same wage, benefits, training and employment protections available to them as professional educators. We identified risk factors for student-related injury and their characteristics among employees in school districts.MethodsWorkers’ compensation data were used to identify incidence and severity of student-related injury. Rates were calculated using negative binomial regression; risk factors were identified using multivariate models to calculate rate ratios (RR) and 95% CIs.ResultsOver 26% of all injuries were student-related; 8% resulted in lost work time. Special and general education assistants experienced significantly increased risk of injury (RR=6.0, CI 5.05 to 7.15; RR=2.07, CI 1.40 to 3.07) as compared with educators. Risk differed by age, gender and school district type. Text analyses categorised student-related injury. It revealed injury from students acting out occurred most frequently (45.4%), whereas injuries involving play with students resulted in the highest percentage of lost-time injuries (17.7%) compared with all interaction categories.ConclusionStudent-inflicted injury to staff occurs frequently and can be severe. Special education and general assistants bear the largest burden of injury compared with educators. A variety of prevention techniques to reduce injury risk and severity, including policy or environmental modifications, may be appropriate. Equal access to risk reduction methods for all staff should be prioritised.
Favorable revascularization therapy in patients with ASPECTS ≤ 5 on DWI in anterior circulation stroke
Authors: Mourand Isabelle , Abergel Eitan , Mantilla Daniel , Ayrignac Xavier , Sacagiu Tzvika , Eker Omer Faruk , Gascou Gregory , Dargazanli Cyril , Riquelme Carlos , Moynier Marinette , Bonafé Alain , Arquizan Caroline , Costalat Vincent 
Published: October 2017

BackgroundA low baseline Alberta Stroke Programme Early CT Score (ASPECTS) is strongly associated with low rates of favorable outcome in patients with acute stroke.ObjectiveTo evaluate the efficacy and safety of revascularization therapy in patient with ASPECTS ≤5 in anterior circulation infarct.MethodsWe retrospectively analyzed 108 consecutive patients presenting low ASPECTS on diffusion-weighted imaging. Sixty patients were treated by mechanical thrombectomy, including 34 patients who received simultaneously intravenous thrombolysis. A control group of 48 patients not eligible for reperfusion therapy gave us a perspective on the natural history. Clinical outcome was evaluated at 90 days using the modified Rankin Scale (mRS) score. Hemicraniectomy after malignant infarction, mortality, and symptomatic intracranial haemorrhage (sICH) were also reported.ResultsThrombolysis in Cerebral Infarction 2b–3 was assessed in 75% of treated patients. Reperfusion therapy led to significantly reduced disability (mRS score 0–2) at 90 days compared with the control group (30% vs 2.1%, p<0.001), hemicraniectomy (3.3% vs 22.9%, p=0.002), and death at 90 days (25% vs 47.9%, p=0.01). The sICH level was similar in treated patients and in the control group (p=0.78). Patients aged ≤70 years in the thrombectomy group had a significantly better clinical outcome than older patients (37.5% vs 10%, p=0.02), regardless of baseline characteristics or recanalization rate.ConclusionsIn patients with acute stroke in the anterior circulation and ASPECTS ≤5 revascularization therapy contributes to a favorable clinical outcome at 90 days, especially in patients younger than 70 years.
Histone Deacetylase Inhibition Enhances the Antitumor Activity of a MEK Inhibitor in Lung Cancer Cells Harboring RAS Mutations
Authors: Yamada Tadaaki , Amann Joseph M. , Tanimoto Azusa , Taniguchi Hirokazu , Shukuya Takehito , Timmers Cynthia , Yano Seiji , Shilo Konstantin , Carbone David P. 
Published: October 2017

Abstract
Non–small cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS–ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle. This is through regulation of apoptotic proteins BIM and FASL and cell-cycle regulators p21Cip1 and p27Kip1. We now show that an HDAC inhibitor affects the expression and localization of FOXO proteins and wanted to determine whether the combination of a MEK inhibitor with an HDAC inhibitor would increase the sensitivity of NSCLC with KRAS mutation. Combined treatment with a MEK inhibitor and an HDAC inhibitor showed synergistic effects on cell metabolic activity of RAS-mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell-cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell-cycle inhibitors p21Cip1 and p27Kip1. These results demonstrate that control of FOXOs localization and expression is critical in RAS-driven lung cancer cells, suggesting that the dual molecular-targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations. Mol Cancer Ther; 17(1); 17–25. ©2017 AACR.
Ceramide Nanoliposomes as a MLKL-Dependent, Necroptosis-Inducing, Chemotherapeutic Reagent in Ovarian Cancer
Authors: Zhang Xuewei , Kitatani Kazuyuki , Toyoshima Masafumi , Ishibashi Masumi , Usui Toshinori , Minato Junko , Egiz Mahy , Shigeta Shogo , Fox Todd , Deering Tye , Kester Mark , Yaegashi Nobuo 
Published: October 2017

Abstract
Ceramides are bioactive lipids that mediate cell death in cancer cells, and ceramide-based therapy is now being tested in dose-escalating phase I clinical trials as a cancer treatment. Multiple nanoscale delivery systems for ceramide have been proposed to overcome the inherent toxicities, poor pharmacokinetics, and difficult biophysics associated with ceramide. Using the ceramide nanoliposomes (CNL), we now investigate the therapeutic efficacy and signaling mechanisms of this nanoscale delivery platform in refractory ovarian cancer. Treatment of ovarian cancer cells with CNL decreased the number of living cells through necroptosis but not apoptosis. Mechanistically, dying SKOV3 ovarian cancer cells exhibit activation of pseudokinase mixed lineage kinase domain-like (MLKL) as evidenced by oligomerization and relocalization to the blebbing membranes, showing necroptotic characteristics. Knockdown of MLKL, but not its upstream protein kinases such as receptor-interacting protein kinases, with siRNA significantly abolished CNL-induced cell death. Monomeric MLKL protein expression inversely correlated with the IC50 values of CNL in distinct ovarian cancer cell lines, suggesting MLKL as a possible determinant for CNL-induced cell death. Finally, systemic CNL administration suppressed metastatic growth in an ovarian cancer cell xenograft model. Taken together, these results suggest that MLKL is a novel pronecroptotic target for ceramide in ovarian cancer models. Mol Cancer Ther; 17(1); 50–59. ©2017 AACR.
Selective and Concentrated Accretion of SN-38 with a CEACAM5-Targeting Antibody–Drug Conjugate (ADC), Labetuzumab Govitecan (IMMU-130)
Authors: Sharkey Robert M. , Govindan Serengulam V. , Cardillo Thomas M. , Donnell Jennifer , Xia Jing , Rossi Edmund A. , Chang Chien-Hsing , Goldenberg David M. 
Published: October 2017

AbstractLabetuzumab govitecan (IMMU-130), an antibody–drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ∼500 or ∼16 μg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1% to 2% injected dose/mL after 5 minutes; overall, approximately 20% was converted to SN-38 and SN-38G. At 1 hour with IMMU-130, 45% to 63% injected dose/mL of the SN-38 was in the serum, with &gt;90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. AUC analysis found that SN-38 levels were approximately 11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130–treated animals. This delivery advantage is amplified &gt;30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. On the basis of the SN-38 equivalents administered, IMMU-130 potentially delivers &gt;300-fold more SN-38 to CEA-producing tumors compared with irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety. Mol Cancer Ther; 17(1); 196–203. ©2017 AACR.
HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma
Authors: Wong So C. , Cheng Weijun , Hamilton Holly , Nicholas Anthony L. , Wakefield Darren H. , Almeida Aaron , Blokhin Andrei V. , Carlson Jeffrey , Neal Zane C. , Subbotin Vladimir , Zhang Guofeng , Hegge Julia , Bertin Stephanie , Trubetskoy Vladimir S. , Rozema David B. , Lewis David L. , Kanner Steven B. 
Published: October 2017

Abstract
Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%–90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an overabundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvβ3 and αvβ5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2α-specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model. Mol Cancer Ther; 17(1); 140–9. ©2017 AACR.
Characterization of Thyroid Disorders in Patients Receiving Immune Checkpoint Inhibition Therapy
Authors: Lee Hyunju , Hodi F. Stephen , Giobbie-Hurder Anita , Ott Patrick A. , Buchbinder Elizabeth I. , Haq Rizwan , Tolaney Sara , Barroso-Sousa Romualdo , Zhang Kevin , Donahue Hilary , Davis Meredith , Gargano Maria E. , Kelley Kristina M. , Carroll Rona S. , Kaiser Ursula B. , Min Le 
Published: October 2017

Abstract
Thyroid disorders have emerged as one of the most common immune-related adverse events associated with anti–PD-1 monotherapy or combination anti–PD-1 and anti–CTLA-4 therapy. This study characterizes and compares the evolution of monotherapy and combination therapy-related thyroid disorders. We analyzed the dynamic evolution of thyroid disorders in 45 patients who developed thyroid disorders following treatment with either anti–PD-1 monotherapy or anti–PD-1 and anti–CTLA-4 combination therapy. The patients presented with thyrotoxicosis or hypothyroidism as the initial presentation of their thyroid disorder. Thyrotoxicosis as the initial presentation occurred in the majority of patients (93% and 56% of the patients receiving combination therapy and monotherapy, respectively). The onset pattern of the thyroid disorder was significantly different between the two groups (P = 0.01). Subsequently, 76% and 90% of the patients with thyrotoxicosis evolved to develop hypothyroidism in the combination and monotherapy groups, respectively. In the combination therapy and monotherapy groups, the median times to onset of thyrotoxicosis and hypothyroidism after first treatment were 21 and 63 days, and 31 and 68 days, respectively. The median time for transition from thyrotoxicosis to hypothyroidism was 42 days in both groups. Our study demonstrates that most thyroid disorders induced by either anti–PD-1 or combination anti–PD-1 and anti–CTLA-4 therapy are thyroiditis. The time to onset of thyrotoxicosis after treatment initiation and evolution of thyrotoxicosis to hypothyroidism was short, emphasizing the importance of close monitoring of thyroid function in these patients. Cancer Immunol Res; 5(12); 1133–40. ©2017 AACR.
Forward Left Ventricular Ejection Fraction: A Simple Risk Marker in Patients With Primary Mitral Regurgitation
Authors: Dupuis Marlène , Mahjoub Haïfa , Clavel Marie‐Annick , Côté Nancy , Toubal Oumhani , Tastet Lionel , Dumesnil Jean G. , O'Connor Kim , Dahou Abdellaziz , Thébault Christophe , Bélanger Catherine , Beaudoin Jonathan , Arsenault Marie , Bernier Mathieu , Pibarot Philippe 
Published: October 2017

Background

The timing of mitral valve surgery in asymptomatic patients with primary mitral regurgitation (
MR
) is controversial. We hypothesized that the forward left ventricular (LV) ejection fraction (
LVEF
; ie,
LV
outflow tract stroke volume divided by
LV
end‐diastolic volume) is superior to the total
LVEF
to predict outcomes in
MR
. The objective of this study was to examine the association between echocardiographic parameters of
MR
severity and
LV
function and outcomes in patients with
MR
.

Methods and Results

The clinical and Doppler‐echocardiographic data of 278 patients with ≥mild
MR
and no class I indication of mitral valve surgery at baseline were retrospectively analyzed. The primary study end point was the composite of mitral valve surgery or death. During a mean follow‐up of 5.4±3.2 years, there were 147 (53%) events: 96 (35%)
MV
surgeries and 66 (24%) deaths. Total
LVEF
and global longitudinal strain were not associated with the occurrence of events, whereas forward
LVEF
(
P
<0.0001) and
LV
end‐systolic diameter (
P
=0.0003) were. After adjustment for age, sex,
MR
severity, Charlson probability, coronary artery disease, and atrial fibrillation, forward
LVEF
remained independently associated with the occurrence of events (adjusted hazard ratio: 1.09, [95% confidence interval]: 1.02–1.17 per 5% decrease;
P
=0.01), whereas
LV
end‐systolic diameter was not (
P
=0.48).

Conclusions

The results of this study suggest that the forward
LVEF
may be superior to the total
LVEF
and
LV
end‐systolic diameter to predict outcomes in patients with primary
MR
. This simple and easily measurable parameter may be useful to improve risk stratification and select the best timing for intervention in patients with primary
MR
.
Prognostic Impact of Subsequent Acute Coronary Syndrome and Unplanned Revascularization on Long‐Term Mortality After an Index Percutaneous Coronary Intervention: A Report From a Japanese Multicenter Registry
Authors: Inohara Taku , Kohsaka Shun , Miyata Hiroaki , Sawano Mitsuaki , Ueda Ikuko , Maekawa Yuichiro , Fukuda Keiichi , Jones Philip G. , Cohen David J. , Zhao Zhenxiang , Spertus John A. , Smolderen Kim G. 
Published: October 2017

Background

Whereas composite end points are often used in clinical trials of percutaneous coronary interventions (
PCI
), the impact of individual components on subsequent survival is incompletely defined. We evaluated the association of subsequent acute coronary syndromes (
ACS
) and unplanned coronary revascularization post‐
PCI
with long‐term survival.

Methods and Results

From 2009 to 2011, the Ki
CS
‐
PCI
(Keio interhospital Cardiovascular Studies) consecutively enrolled patients undergoing
PCI
in 14 Japanese teaching hospitals. We identified patients who experienced
ACS
or unplanned coronary revascularization following their index
PCI
and compared subsequent survival during the 2‐year follow‐up period using propensity‐matched cohorts of patients who did and did not experience these events. Cox proportional hazard models were used to assess 2‐year all‐cause mortality. Because unstable angina is less severe than acute myocardial infarction, we also generated a separate propensity‐matched cohort for
UA
post‐
PCI
. Among 3348
PCI
patients (mean age, 67.5±10.7 years; 79.7% male), 214 (6.4%) experienced a subsequent
ACS
(168 events [78.5%] were unstable angina), and 198 (5.9%) underwent unplanned revascularization. In the propensity‐matched cohorts, patients with a subsequent
ACS
admission had an increased risk of mortality as compared with those without (hazard ratio, 4.73; 95% confidence interval=1.35–16.6;
P
=0.015), whereas those with an unplanned revascularization did not have significantly higher risk (hazard ratio, 2.97; 95% confidence interval=0.57–14.3;
P
=0.19). Among unstable angina events, no association with mortality was observed (hazard ratio, 1.39; 95% confidence interval=0.48–4.00;
P
=0.54).

Conclusions

In the Ki
CS
‐
PCI
registry, the incidence of a subsequent
ACS
was associated with higher mortality, but this association was less apparent after unplanned coronary revascularization or unstable angina. The prognostic implications of different outcomes in a composite end point should be considered when interpreting the results of clinical trials in
PCI
.
Attenuated Superoxide Dismutase 2 Activity Induces Atherosclerotic Plaque Instability During Aging in Hyperlipidemic Mice
Authors: Vendrov Aleksandr E. , Stevenson Mark D. , Alahari Samthosh , Pan Hua , Wickline Samuel A. , Madamanchi Nageswara R. , Runge Marschall S. 
Published: October 2017

Background

Atherosclerosis progression during aging culminates in the development of vulnerable plaques, which may increase the risk of cardiovascular events. Increased generation and/or decreased scavenging of reactive oxygen species in the vascular wall are major contributors to atherogenesis. We previously showed that superoxide dismutase 2 deficiency increased vascular oxidative stress and reduced aortic compliance in aged wild‐type mice and that young
Apoe
−/−
/
Sod2
+/−
had increased mitochondrial
DNA
damage and atherosclerosis versus young
Apoe
−/−
mice. Here we investigated the effects of superoxide dismutase 2 deficiency on atherosclerosis progression and plaque morphology in middle‐aged
Apoe
−/−
mice.

Methods and Results

Compared with
Apoe
−/−
, middle‐aged
Apoe
−/−
/
Sod2
+/−
mice had increased vascular wall reactive oxygen species (
P
<0.05) and higher atherosclerotic lesion area (
P
<0.001). The atherosclerotic plaques in middle‐aged
Apoe
−/−
/
Sod2
+/−
mice had an increased necrotic core with higher inflammatory cell infiltration, a thinned fibrous cap with depleted smooth muscle content, and intraplaque hemorrhage. In addition, the plaque shoulder area had higher levels of calpain‐2, caspase‐3, and matrix metalloproteinase‐2 in intimal smooth muscle cells and depleted fibrous cap collagen. Targeting mitochondrial reactive oxygen species with Mito
TEMPO
attenuated features of atherosclerotic plaque vulnerability in middle‐aged
Apoe
−/−
/
Sod2
+/−
mice by lowering expression of calpain‐2, caspase‐3, and matrix metalloproteinase‐2 and decreasing smooth muscle cell apoptosis and matrix degradation.

Conclusions
Enhanced mitochondrial oxidative stress under hyperlipidemic conditions in aging induces plaque instability, in part by increasing smooth muscle cell apoptosis, necrotic core expansion, and matrix degradation. Targeting mitochondrial reactive oxygen species or its effectors may be a viable therapeutic strategy to prevent aging‐associated and oxidative stress–related atherosclerosis complications.