bluuebunny/crossref_metadata_2025_split huggingface dataset:
Better patient safety: implementing exploration and exploitation learning in daily medical practice
Authors: Kobo Greenhut Ayala , Magnezi Racheli , Ben Shlomo Izhar 
Published: September 2017

BackgroundCurrent medical daily practice relies on guidelines, protocols and procedures (GPPs), which require exploitation. However, diagnosis, treatment, risk management and process improvements require exploration. Physician are often unable to switch between exploitation and exploration. This study tested a new approach to facilitate switching that included (1) a new ‘thinking protocol’ that encouraged leaping from exploitation to exploration and (2) a GPP that encouraged leaping from exploration to exploitation.MethodTwo hundred students were divided into four groups. The groups received a set of tasks that required switching between exploitation and exploration. Three groups received the thinking protocol, the GPP, or both, and the fourth group served as control.ResultsWith each additional task, all groups increased exploitative tendency(p<0.0001). The two groups with the thinking protocol leaped from exploitation to exploration (p<0.0001); the other two groups remained in exploitation (p=0.1173, p=0.0758). For the groups that employed exploration learning, the group that received the GPP switched back to exploitation (p<0.0001), but the other group remained in exploration (p=0.2363).ConclusionDespite the importance of timely leaping between exploration and exploitation, in some events, medical teams fail to make the appropriate leap. We suggest to use our novel approach and to encourage the leaping between exploration and exploitation in daily medical practice, to enable the prevention of medical errors and to enhance the effectiveness of risk managements and process improvements.
Ischaemic heart disease in the former Soviet Union 1990–2015 according to the Global Burden of Disease 2015 Study
Authors: Murphy Adrianna , Johnson Catherine O , Roth Gregory A , Forouzanfar Mohammad H , Naghavi Mohsen , Ng Marie , Pogosova Nana , Vos Theo , Murray Christopher J L , Moran Andrew E 
Published: September 2017

ObjectiveThe objective of this study was to compare ischaemic heart disease (IHD) mortality and risk factor burden across former Soviet Union (fSU) and satellite countries and regions in 1990 and 2015.MethodsThe fSU and satellite countries were grouped into Central Asian, Central European and Eastern European regions. IHD mortality data for men and women of any age were gathered from national vital registration, and age, sex, country, year-specific IHD mortality rates were estimated in an ensemble model. IHD morbidity and mortality burden attributable to risk factors was estimated by comparative risk assessment using population attributable fractions.ResultsIn 2015, age-standardised IHD death rates in Eastern European and Central Asian fSU countries were almost two times that of satellite states of Central Europe. Between 1990 and 2015, rates decreased substantially in Central Europe (men −43.5% (95% uncertainty interval −45.0%, −42.0%); women −42.9% (−44.0%, −41.0%)) but less in Eastern Europe (men −5.6% (−9.0, –3.0); women −12.2% (−15.5%, −9.0%)). Age-standardised IHD death rates also varied within regions: within Eastern Europe, rates decreased −51.7% in Estonian men (−54.0, −47.0) but increased +19.4% in Belarusian men (+12.0, +27.0). High blood pressure and cholesterol were leading risk factors for IHD burden, with smoking, body mass index, dietary factors and ambient air pollution also ranking high.ConclusionsSome fSU countries continue to experience a high IHD burden, while others have achieved remarkable reductions in IHD mortality. Control of blood pressure, cholesterol and smoking are IHD prevention priorities.
Relationships between ultrasound enthesitis, disease activity and axial radiographic structural changes in patients with early spondyloarthritis: data from DESIR cohort
Authors: Ruyssen-Witrand Adeline , Jamard Bénédicte , Cantagrel Alain , Nigon Delphine , Loeuille Damien , Degboe Yannick , Constantin Arnaud 
Published: September 2017

BackgroundTo search for association between ultrasound (US) enthesis abnormalities and disease activity, spine and sacro-iliac joints (SIJ) MRI inflammatory lesions and spine structural changes in a cohort of patients suspected for axial spondyloarthritis (SpA).MethodsPatients:Of 708 patients included in the DESIR(Devenir des Spondyloarthrites Indifférenciées Récentes) cohort, 402 had an US enthesis assessment and were selected for this study.Imaging:Achilles, lateral epicondyles, superior patellar ligament, inferior patellar ligament entheses were systematically US scanned and abnormalities were summed in US structural and power Doppler (PDUS) scores. Spine radiographs, SIJ and spine MRI scans were centrally scored modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), presence of MRI sacro-iliitis, Spondyloarthritis Research Consortium of Canada and Berlin scores.Analysis:The associations between the US structural/PDUS scores and disease activity, C reactive protein (CRP), MRI SIJ and spine inflammatory lesions and mSASSS were tested by Spearman's correlation tests.ResultsAmong the 402 patients included (median age: 33.5 years, males: 48.5%), 55% had US enthesis structural abnormalities while 14% had PDUS abnormalities. There was no association between US scores and Bath Ankylosing Spondylitis Disease Activity Index, CRP or inflammatory lesions on SIJ and spine MRI. There was a correlation between US structural and PDUS scores and the mSASSS (respectively, r=0.151, p=0.005; r=0.143, p=0.007). The proportion of patients with syndesmophytes was higher in the case of US enthesophytes (26% of syndesmophytes vs 6% in the absence of US enthesophytes, p<0.0001).ConclusionWhile the US abnormalities do not seem to be a helpful tool for monitoring disease activity in axial SpA, US enthesophytes, strongly associated with axial syndesmophytes, might be a marker of interest for disease severity.Trial registration numberNCT01648907, date of registration : 20 July 2012.
Validity, responsiveness and minimum clinically important difference of the incremental shuttle walk in idiopathic pulmonary fibrosis: a prospective study
Authors: Nolan Claire M , Delogu Veronica , Maddocks Matthew , Patel Suhani , Barker Ruth E , Jones Sarah E , Kon Samantha S C , Maher Toby M , Cullinan Paul , Man William D-C 
Published: September 2017

The incremental shuttle walk (ISW) is well validated in COPD but limited psychometric data restrict its use in idiopathic pulmonary fibrosis (IPF). Study 1: 50 patients performed the ISW and 6 min walk test (6MWT). Study 2: 72 patients completed the ISW before and after pulmonary rehabilitation (PR). The ISW correlated strongly with 6MWT distance (r=0.81,p<0.0001). Mean (95% confidence interval) improvement in ISW with PR was 54 (38 to 70) m with an effect size of 0.29. Distribution-based and anchor-based minimum clinically important difference (MCID) estimates ranged from 31 to 46 m. The ISW is valid and responsive in IPF, with an anchor-based MCID estimate similar to that observed in chronic obstructive pulmonary disease.Trial registration numberPre-results; NCT02530736, NCT02436278.
Seasonal Variation of Trauma in Western Massachusetts: Fact or Folklore?
Authors: Nahmias Jeffry , Poola Shiva , Doben Andrew , Garb Jane , Gross Ronald I 
Published: September 2017

BackgroundPrevious studies have demonstrated a significant relationship between weather or seasons and total trauma admissions. We hypothesized that specific mechanisms such as penetrating trauma, motor vehicle crashes, and motorcycle crashes (MCCs) occur more commonly during the summer, while more falls and suicide attempts during winter.MethodsA retrospective review of trauma admissions to a single Level I trauma center in Springfield, Massachusetts from 01/2010 through 12/2015 was performed. Basic demographics including age, Injury Severity Score (ISS), and length of stay were collected. Linear regression analysis was used to test the association between monthly admission rates and season, year, injury class, and mechanism of injury, and whether seasonal variation trends were different according to injury class or mechanism.ResultsA total of 8886 admissions had a mean age of 44.6 and mean ISS of 11.9. Regression analysis showed significant seasonal variation in blunt compared with penetrating trauma (p<0.001), MCC (p<0.001), and falls (p=0.002). In addition, seasonal variation differed according to injury class or mechanism. There were significantly lower rates of MCCs in winter compared with all other seasons and conversely higher rates of total falls in winter compared with other seasons.DiscussionA significant seasonal variation in blunt trauma, MCC, and falls was observed. This has potential ramifications for resource allocation, including trauma prevention programs geared toward mechanisms of injury with significant seasonal variation.Level of evidenceRetrospective Review, Level IV.
Beneficial effects of exercise training in heart failure are lost in male diabetic rats
Authors: Boudia Dalila , Domergue Valérie , Mateo Philippe , Fazal Loubina , Prud’homme Mathilde , Prigent Héloïse , Delcayre Claude , Cohen-Solal Alain , Garnier Anne , Ventura-Clapier Renée , Samuel Jane-Lise 
Published: September 2017

Exercise training has been demonstrated to have beneficial effects in patients with heart failure (HF) or diabetes. However, it is unknown whether diabetic patients with HF will benefit from exercise training. Male Wistar rats were fed either a standard (Sham, n = 53) or high-fat, high-sucrose diet ( n = 66) for 6 mo. After 2 mo of diet, the rats were already diabetic. Rats were then randomly subjected to either myocardial infarction by coronary artery ligation (MI) or sham operation. Two months later, heart failure was documented by echocardiography and animals were randomly subjected to exercise training with treadmill for an additional 8 wk or remained sedentary. At the end, rats were euthanized and tissues were assayed by RT-PCR, immunoblotting, spectrophotometry, and immunohistology. MI induced a similar decrease in ejection fraction in diabetic and lean animals but a higher premature mortality in the diabetic group. Exercise for 8 wk resulted in a higher working power developed by MI animals with diabetes and improved glycaemia but not ejection fraction or pathological phenotype. In contrast, exercise improved the ejection fraction and increased adaptive hypertrophy after MI in the lean group. Trained diabetic rats with MI were nevertheless able to develop cardiomyocyte hypertrophy but without angiogenic responses. Exercise improved stress markers and cardiac energy metabolism in lean but not diabetic-MI rats. Hence, following HF, the benefits of exercise training on cardiac function are blunted in diabetic animals. In conclusion, exercise training only improved the myocardial profile of infarcted lean rats fed the standard diet.NEW & NOTEWORTHY Exercise training is beneficial in patients with heart failure (HF) or diabetes. However, less is known of the possible benefit of exercise training for HF patients with diabetes. Using a rat model where both diabetes and MI had been induced, we showed that 2 mo after MI, 8 wk of exercise training failed to improve cardiac function and metabolism in diabetic animals in contrast to lean animals.
miR-193b–Regulated Signaling Networks Serve as Tumor Suppressors in Liposarcoma and Promote Adipogenesis in Adipose-Derived Stem Cells
Authors: Mazzu Ying Z. , Hu Yulan , Soni Rajesh K. , Mojica Kelly M. , Qin Li-Xuan , Agius Phaedra , Waxman Zachary M. , Mihailovic Aleksandra , Socci Nicholas D. , Hendrickson Ronald C. , Tuschl Thomas , Singer Samuel 
Published: September 2017

Abstract
Well-differentiated and dedifferentiated liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo. Deep RNA sequencing on 93 WDLS, 145 DDLS, and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared with normal fat. Reintroduction of miR-193b induced apoptosis in liposarcoma cells and promoted adipogenesis in human adipose-derived stem cells (ASC). Integrative transcriptomic and proteomic analysis of miR-193b–target networks identified novel direct targets, including CRK-like proto-oncogene (CRKL) and focal adhesion kinase (FAK). miR-193b was found to regulate FAK–SRC–CRKL signaling through CRKL and FAK. miR-193b also stimulated reactive oxygen species signaling by targeting the antioxidant methionine sulfoxide reductase A to modulate liposarcoma cell survival and ASC differentiation state. Expression of miR-193b in liposarcoma cells was downregulated by promoter methylation, resulting at least in part from increased expression of the DNA methyltransferase DNMT1 in WDLS/DDLS. In vivo, miR-193b mimetics and FAK inhibitor (PF-562271) each inhibited liposarcoma xenograft growth. In summary, miR-193b not only functions as a tumor suppressor in liposarcoma but also promotes adipogenesis in ASC. Furthermore, this study reveals key tyrosine kinase and DNA methylation pathways in liposarcoma, some with immediate implications for therapeutic exploration. Cancer Res; 77(21); 5728–40. ©2017 AACR.
CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer
Authors: He Weiling , Zhang Hui , Han Fei , Chen Xinlin , Lin Run , Wang Wei , Qiu Haibo , Zhuang Zhenhong , Liao Qi , Zhang Weijing , Cai Qinbo , Cui Yongmei , Jiang Wenting , Wang Han , Ke Zunfu 
Published: September 2017

Abstract
The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT+ was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell–gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T-cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T-cell metabolism and IFNγ production, whereas CD155 overexpression inhibited T-cell metabolism and IFNγ production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice. Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer. Cancer Res; 77(22); 6375–88. ©2017 AACR.
KDM4 Inhibition Targets Breast Cancer Stem–like Cells
Authors: Metzger Eric , Stepputtis Stella S. , Strietz Juliane , Preca Bogdan-Tiberius , Urban Sylvia , Willmann Dominica , Allen Anita , Zenk Fides , Iovino Nicola , Bronsert Peter , Proske Amelie , Follo Marie , Boerries Melanie , Stickeler Elmar , Xu Jiangchun , Wallace Michael B. , Stafford Jeffrey A. , Kanouni Toufike , Maurer Jochen , Schüle Roland 
Published: September 2017

Abstract
Traditional treatments for breast cancer fail to address therapy-resistant cancer stem–like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem–like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900–12. ©2017 AACR.
Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites
Authors: Feng Shuang , Bowden Neil , Fragiadaki Maria , Souilhol Celine , Hsiao Sarah , Mahmoud Marwa , Allen Scott , Pirri Daniela , Ayllon Blanca Tardajos , Akhtar Shamima , Thompson A.A. Roger , Jo Hanjoong , Weber Christian , Ridger Victoria , Schober Andreas , Evans Paul C. 
Published: September 2017

Objective—
Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and inflammation that promote lesion initiation. The transcription factor HIF1α (hypoxia-inducible factor 1α) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1α activation and the contribution of this noncanonical pathway to lesion initiation.

Approach and Results—
Quantitative polymerase chain reaction and en face staining revealed that HIF1α was expressed preferentially at low shear stress regions of porcine and murine arteries. Low shear stress induced HIF1α in cultured EC in the presence of atmospheric oxygen. The mechanism involves the transcription factor nuclear factor-κB that induced HIF1α transcripts and induction of the deubiquitinating enzyme Cezanne that stabilized HIF1α protein. Gene silencing revealed that HIF1α enhanced proliferation and inflammatory activation in EC exposed to low shear stress via induction of glycolysis enzymes. We validated this observation by imposing low shear stress in murine carotid arteries (partial ligation) that upregulated the expression of HIF1α, glycolysis enzymes, and inflammatory genes and enhanced EC proliferation. EC-specific genetic deletion of HIF1α in hypercholesterolemic apolipoprotein E–defecient mice reduced inflammation and endothelial proliferation in partially ligated arteries, indicating that HIF1α drives inflammation and vascular dysfunction at low shear stress regions.

Conclusions—
Mechanical low shear stress activates HIF1α at atheroprone regions of arteries via nuclear factor-κB and Cezanne. HIF1α promotes atherosclerosis initiation at these sites by inducing excessive EC proliferation and inflammation via the induction of glycolysis enzymes.
Independent and Synergistic Associations of Biomarkers of Vitamin D Status With Risk of Coronary Heart Disease
Authors: Qi Lu , Ma Wenjie , Heianza Yoriko , Zheng Yan , Wang Tiange , Sun Dianjianyi , Rimm Eric B. , Hu Frank B. , Giovannucci Edward , Albert Christine M. , Rexrode Kathryn M. , Manson JoAnn E. 
Published: September 2017

Objective—
To comprehensively evaluate the independent associations and potential interactions of vitamin D–related biomarkers including total and bioavailable 25-hydroxyvitamin D (25OHD), VDBP (vitamin D binding protein), and parathyroid hormone (PTH) with risk of coronary heart disease (CHD).

Approach and Results—

We prospectively identified incident cases of nonfatal myocardial infarction and fatal CHD among women in the Nurses’ Health Study during 20 years of follow-up (1990–2010). Using risk-set sampling, 1 to 2 matched controls were selected for each case. The analysis of 25OHD and PTH included 382 cases and 575 controls; the analysis of VDBP included 396 cases and 398 controls. After multivariate adjustment, plasma levels of total 25OHD, bioavailable 25OHD, and PTH were not significantly associated with CHD risk. VDBP was associated with a lower CHD risk with an extreme-quartile odds ratio of 0.60 (95% confidence interval, 0.39–0.92;
P
trend=0.02). When examining the biomarkers jointly, a significant, inverse association between 25OHD and CHD was observed among participants with higher PTH levels (
P
for interaction=0.02). The odds ratio (95% confidence interval) comparing the highest quartile of 25OHD to lowest was 0.43 (0.23–0.82;
P
trend=0.003) when PTH levels were above population median (35.3 pg/mL), whereas among the rest of participants the corresponding odds ratio (95% confidence interval) was 1.28 (0.70–2.36;
P
trend=0.43).

Conclusions—
Our data suggest that higher 25OHD levels were associated with a lower CHD risk when PTH levels were high, whereas no association was observed for participants with low PTH levels. VDBP but not bioavailable 25OHD was independently associated with lower CHD risk.
ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels
Authors: Trigueros-Motos Laia , van Capelleveen Julian C. , Torta Federico , Castaño David , Zhang Lin-Hua , Chai Ee Chu , Kang Martin , Dimova Lidiya G. , Schimmel Alinda W.M. , Tietjen Ian , Radomski Chris , Tan Liang Juin , Thiam Chung Hwee , Narayanaswamy Pradeep , Wu Daniel Heqing , Dorninger Fabian , Yakala Gopala Krishna , Barhdadi Amina , Angeli Veronique , Dubé Marie-Pierre , Berger Johannes , Dallinga-Thie Geesje M. , Tietge Uwe J.F. , Wenk Markus R. , Hayden Michael R. , Hovingh G. Kees , Singaraja Roshni R. 
Published: September 2017

Objective—

High-density lipoproteins (HDL) are considered to protect against atherosclerosis in part by facilitating the removal of cholesterol from peripheral tissues. However, factors regulating lipid efflux are incompletely understood. We previously identified a variant in adenosine triphosphate–binding cassette transporter A8 (
ABCA8
) in an individual with low HDL cholesterol (HDLc). Here, we investigate the role of ABCA8 in cholesterol efflux and in regulating HDLc levels.

Approach and Results—

We sequenced
ABCA8
in individuals with low and high HDLc and identified, exclusively in low HDLc probands, 3 predicted deleterious heterozygous
ABCA8
mutations (p.Pro609Arg [P609R], IVS17-2 A>G and p.Thr741Stop [T741X]). HDLc levels were lower in heterozygous mutation carriers compared with first-degree family controls (0.86±0.34 versus 1.17±0.26 mmol/L;
P
=0.005). HDLc levels were significantly decreased by 29% (
P
=0.01) in
Abca8b
−/−
mice on a high-cholesterol diet compared with wild-type mice, whereas hepatic overexpression of human
ABCA8
in mice resulted in significant increases in plasma HDLc and the first steps of macrophage-to-feces reverse cholesterol transport. Overexpression of wild-type but not mutant ABCA8 resulted in a significant increase (1.8-fold;
P
=0.01) of cholesterol efflux to apolipoprotein AI in vitro. ABCA8 colocalizes and interacts with adenosine triphosphate–binding cassette transporter A1 and further potentiates adenosine triphosphate–binding cassette transporter A1–mediated cholesterol efflux.

Conclusions—
ABCA8 facilitates cholesterol efflux and modulates HDLc levels in humans and mice.