bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paramedics' views on their seizure management learning needs: a qualitative study in England
Authors: Sherratt Frances C , Snape Darlene , Goodacre Steve , Jackson Mike , Pearson Mike , Marson Anthony G , Noble Adam J 
Published: January 2017

IntroductionThe UK ambulance service often attends to suspected seizures. Most persons attended to will not require the facilities of a hospital emergency department (ED) and so should be managed at scene or by using alternative care pathways. Most though are transported to ED. One factor that helps explain this is paramedics can have low confidence in managing seizures.ObjectivesWith a view to ultimately developing additional seizure management training for practicing paramedics, we explored their learning needs, delivery preferences and potential drivers and barriers to uptake and effectiveness.Design and settingSemistructured interviews were conducted with a purposive sample of paramedics from the English ambulance service. Interviews were transcribed and thematically analysed.ParticipantsA diverse sample of 19 professionals was recruited from 5 different ambulance NHS trusts and the College of Paramedics.ResultsParticipants said seizure management was neglected within basic and postregistration paramedic training. Most welcomed additional learning opportunities and identified gaps in knowledge. This included how to differentiate between seizure types and patients that do and do not need ED. Practical, interactive e-learning was deemed the most preferable delivery format. To allow paramedics to fully implement any increase in skill resulting from training, organisational and structural changes were said to be needed. This includes not penalising paramedics for likely spending longer on scene.ConclusionsThis study provides the first evidence on the learning needs and preferences of paramedics regarding seizures. It can be used to inform the development of a bespoke training programme for paramedics. Future research should develop and then assess the benefit such training has on paramedic confidence and on the quality of care they offer to seizure patients.
What aspects of intentional rounding work in hospital wards, for whom and in what circumstances? A realist evaluation protocol
Authors: Harris Ruth , Sims Sarah , Levenson Ros , Gourlay Stephen , Ross CBE Fiona , Davies Nigel , Brearley Sally , Favato Giampiero , Grant Robert 
Published: January 2017

IntroductionIntentional rounding (IR) is a structured process whereby nurses in hospitals carry out regular checks, usually hourly, with individual patients using a standardised protocol to address issues of positioning, pain, personal needs and placement of items. The widespread implementation of IR across the UK has been driven by the recommendations of the Francis Inquiry although empirical evidence of its effectiveness is poor. This paper presents a protocol of a multimethod study using a realist evaluation approach to investigate the impact and effectiveness of IR in hospital wards on the organisation, delivery and experience of care from the perspective of patients, their family members and staff.Methods and analysisThe study will be conducted in four phases. Phase 1: theory development using realist synthesis to generate hypotheses about what the mechanisms of IR may be, what particular groups may benefit most or least and what contextual factors might be important to its success or failure which will be tested in subsequent phases of the study. Phase 2: a national survey of all NHS acute trusts to explore how IR is implemented and supported across England. Phase 3: case studies to explore how IR is implemented ‘on the ground’, including individual interviews with patients, family members and staff, non-participant observation, retrieval of routinely collected patient outcomes and cost analysis. Phase 4: accumulative data analysis across the phases to scrutinise data for patterns of congruence and discordance and develop an overall evaluation of what aspects of IR work, for whom and in what circumstances.Ethics and disseminationThe study has been approved by NHS South East Coast—Surrey Research Ethics Committee. Findings will be published in a wide range of outputs targeted at key audiences, including patient and carer organisations, nursing staff and healthcare managers.
Meat intake and risk of diverticulitis among men
Authors: Cao Yin , Strate Lisa L , Keeley Brieze R , Tam Idy , Wu Kana , Giovannucci Edward L , Chan Andrew T 
Published: January 2017

ObjectiveDiverticulitis is a common disease with a substantial clinical and economic burden. Besides dietary fibre, the role of other foods in the prevention of diverticulitis is underexplored.DesignWe prospectively examined the association between consumption of meat (total red meat, red unprocessed meat, red processed meat, poultry and fish) with risk of incident diverticulitis among 46 461 men enrolled in the Health Professionals Follow-Up Study (1986–2012). Cox proportional hazards models were used to compute relative risks (RRs) and 95% CIs.ResultsDuring 651 970 person-years of follow-up, we documented 764 cases of incident diverticulitis. Compared with men in the lowest quintile (Q1) of total red meat consumption, men in the highest quintile (Q5) had a multivariable RR of 1.58 (95% CI 1.19 to 2.11; p for trend=0.01). The increase in risk was non-linear, plateauing after six servings per week (p for non-linearity=0.002). The association was stronger for unprocessed red meat (RR for Q5 vs Q1: 1.51; 95% CI 1.12 to 2.03; p for trend=0.03) than for processed red meat (RR for Q5 vs Q1: 1.03; 95% CI 0.78 to 1.35; p for trend=0.26). Higher consumption of poultry or fish was not associated with risk of diverticulitis. However, the substitution of poultry or fish for one serving of unprocessed red meat per day was associated with a decrease in risk of diverticulitis (multivariable RR 0.80; 95% CI 0.63 to 0.99).ConclusionsRed meat intake, particularly unprocessed red meat, was associated with an increased risk of diverticulitis. The findings provide practical dietary guidance for patients at risk of diverticulitis.
Coeliac disease screening is suboptimal in a tertiary gastroenterology setting
Authors: Iskandar Heba , Gray Darrell M , Vu Hongha , Mirza Faiz , Rude Mary Katherine , Regan Kara , Abdalla Adil , Gaddam Srinivas , Almaskeen Sami , Mello Michael , Marquez Evelyn , Meyer Claire , Bolkhir Ahmed , Kanuri Navya , Sayuk Gregory , Gyawali C Prakash 
Published: January 2017

ABSTRACTBackground and aimsCoeliac disease (CD) is widely prevalent in North America, but case-finding techniques currently used may not be adequate for patient identification. We aimed to determine the adequacy of CD screening in an academic gastroenterology (GI) practice.MethodsConsecutive initial visits to a tertiary academic GI practice were surveyed over a 3-month period as a fellow-initiated quality improvement project. All electronic records were reviewed to look for indications for CD screening according to published guidelines. The timing of screening was noted (before or after referral), as well as the screening method (serology or biopsy). Data were analysed to compare CD screening practices across subspecialty clinics.Results616 consecutive patients (49±0.6 years, range 16–87 years, 58.5% females, 94% Caucasian) fulfilled inclusion criteria. CD testing was indicated in 336 (54.5%), but performed in only 145 (43.2%). The need for CD screening was highest in luminal GI and inflammatory bowel disease clinics, followed by biliary and hepatology clinics (p&lt;0.0001); CD screening rate was highest in the luminal GI clinic (p=0.002). Of 145 patients screened, 4 patients (2.4%) had serology consistent with CD, of which 2 were proven by duodenal biopsy. Using this proportion, an additional 5 patients might have been diagnosed in 191 untested patients with indications for CD screening.ConclusionsMore than 50% of patients in a tertiary GI clinic have indications for CD screening, but &lt;50% of indicated cases are screened. Case-finding techniques therefore are suboptimal, constituting a gap in patient care and an important target for future quality improvement initiatives.
Non-alcoholic fatty pancreas disease
Authors: Alempijevic Tamara , Dragasevic Sanja , Zec Simon , Popovic Dragan , Milosavljevic Tomica 
Published: January 2017

ABSTRACTObesity is a growing problem worldwide and disorders associated with excess body fat including the metabolic syndrome, type 2 diabetes mellitus (T2DM), cardiovascular disease and malignant neoplasms are becoming a major cause of morbidity and mortality. Over the past decade, a vast amount of research has furthered our understanding of non-alcoholic fatty liver disease; however, only recently pancreatic fat infiltration is coming to the forefront of investigation. Termed non-alcoholic fatty pancreas disease (NAFPD), it is becoming evident that it has important associations with other diseases of obesity. It appears to arise as obesity progresses and after an initial phase of pancreatic hypertrophy and hyperplasia, fatty infiltration becomes apparent. Various studies have demonstrated that NAFPD may exacerbate the severity of acute pancreatitis, promote pancreatic dysfunction associated with insulin resistance and T2DM, and even have links to the development of pancreatic carcinoma, and therefore, it must be investigated in further detail.
Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra
Authors: Chmielecki Juliann , Bailey Mark , He Jie , Elvin Julia , Vergilio Jo-Anne , Ramkissoon Shakti , Suh James , Frampton Garrett M. , Sun James X. , Morley Samantha , Spritz Daniel , Ali Siraj , Gay Laurie , Erlich Rachel L. , Ross Jeffrey S. , Buxhaku Joana , Davies Hilary , Faso Vinny , Germain Alexis , Glanville Blair , Miller Vincent A. , Stephens Philip J. , Janeway Katherine A. , Maris John M. , Meshinchi Soheil , Pugh Trevor J. , Shern Jack F. , Lipson Doron 
Published: January 2017

Abstract
Pediatric cancers are generally characterized by low mutational burden and few recurrently mutated genes. Recent studies suggest that genomic alterations may help guide treatment decisions and clinical trial selection. Here, we describe genomic profiles from 1,215 pediatric tumors representing sarcomas, extracranial embryonal tumors, brain tumors, hematologic malignancies, carcinomas, and gonadal tumors. Comparable published datasets identified similar frequencies of clinically relevant alterations, validating this dataset as biologically relevant. We identified novel ALK fusions in a neuroblastoma (BEND5–ALK) and an astrocytoma (PPP1CB–ALK), novel BRAF fusions in an astrocytoma (BCAS1–BRAF) and a ganglioglioma (TMEM106B–BRAF), and a novel PAX3–GLI2 fusion in a rhabdomyosarcoma. Previously characterized ALK, NTRK1, and PAX3 fusions were observed in unexpected malignancies, challenging the "disease-specific" alterations paradigm. Finally, we identified recurrent variants of unknown significance in MLL3 and PRSS1 predicted to have functional impact. Data from these 1,215 tumors are publicly available for discovery and validation. Cancer Res; 77(2); 509–19. ©2017 AACR.
Weight Fluctuation and Cancer Risk in Postmenopausal Women: The Women's Health Initiative
Authors: Welti Laura M. , Beavers Daniel P. , Caan Bette J. , Sangi-Haghpeykar Haleh , Vitolins Mara Z. , Beavers Kristen M. 
Published: January 2017

AbstractBackground: Weight cycling, defined by an intentional weight loss and subsequent regain, commonly occurs in overweight and obese women and is associated with some negative health outcomes. We examined the role of various weight-change patterns during early to mid-adulthood and associated risk of highly prevalent, obesity-related cancers (breast, endometrial, and colorectal) in postmenopausal women.Methods: A total of 80,943 postmenopausal women (age, 63.4 ± 7.4 years) in the Women's Health Initiative Observational Study were categorized by self-reported weight change (weight stable; weight gain; lost weight; weight cycled [1–3, 4–6, 7–10, &gt;10 times]) during early to mid-adulthood (18–50 years). Three site-specific associations were investigated using Cox proportional hazard models [age, race/ethnicity, income, education, smoking, alcohol, physical activity, hormone therapy, diet, and body mass index (BMI)].Results: A total of 7,464 (breast = 5,564; endometrial = 788; and colorectal = 1,290) incident cancer cases were identified between September 1994 and August 2014. Compared with weight stability, weight gain was significantly associated with risk of breast cancer [hazard ratio (HR), 1.11; 1.03–1.20] after adjustment for BMI. Similarly, weight cycling was significantly associated with risk of endometrial cancer (HR = 1.23; 1.01–1.49). Weight cycling “4 to 6 times” was most consistently associated with cancer risk, showing a 38% increased risk for endometrial cancer [95% confidence interval (CI), 1.08–1.76] compared with weight stable women.Conclusions: Weight gain and weight cycling were positively associated with risk of breast and endometrial cancer, respectively.Impact: These data suggest weight cycling and weight gain increase risk of prevalent cancers in postmenopausal women. Adopting ideal body-weight maintenance practices before and after weight loss should be encouraged to reduce risk of incident breast and endometrial cancers. Cancer Epidemiol Biomarkers Prev; 26(5); 779–86. ©2017 AACR.
A Novel Murine GITR Ligand Fusion Protein Induces Antitumor Activity as a Monotherapy That Is Further Enhanced in Combination with an OX40 Agonist
Authors: Leyland Rebecca , Watkins Amanda , Mulgrew Kathy A. , Holoweckyj Nicholas , Bamber Lisa , Tigue Natalie J. , Offer Emily , Andrews John , Yan Li , Mullins Stefanie , Oberst Michael D. , Coates Ulrichsen Jane , Leinster David A. , McGlinchey Kelly , Young Lesley , Morrow Michelle , Hammond Scott A. , Mallinder Philip , Herath Athula , Leow Ching Ching , Wilkinson Robert W. , Stewart Ross 
Published: January 2017

Abstract
Purpose: To generate and characterize a murine GITR ligand fusion protein (mGITRL-FP) designed to maximize valency and the potential to agonize the GITR receptor for cancer immunotherapy.
Experimental Design: The EC50 value of the mGITRL-FP was compared with an anti-GITR antibody in an in vitro agonistic cell–based reporter assay. We assessed the impact of dose, schedule, and Fc isotype on antitumor activity and T-cell modulation in the CT26 tumor model. The activity of the mGITRL-FP was compared with an agonistic murine OX40L-FP targeting OX40, in CT26 and B16F10-Luc2 tumor models. Combination of the mGITRL-FP with antibodies targeting PD-L1, PD-1, or CTLA-4 was analyzed in mice bearing CT26 tumors.
Results: The mGITRL-FP had an almost 50-fold higher EC50 value compared with an anti-murine GITR antibody. Treatment of CT26 tumor-bearing mice with mGITRL-FP–mediated significant antitumor activity that was dependent on isotype, dose, and duration of exposure. The antitumor activity could be correlated with the increased proliferation of peripheral CD8+ and CD4+ T cells and a significant decrease in the frequency of intratumoral Tregs. The combination of mGITRL-FP with mOX40L-FP or checkpoint inhibitor antagonists enhanced antitumor immunity above that of monotherapy treatment.
Conclusions: These results suggest that therapeutically targeting GITR represents a unique approach to cancer immunotherapy and suggests that a multimeric fusion protein may provide increased agonistic potential versus an antibody. In addition, these data provide, for the first time, early proof of concept for the potential combination of GITR targeting agents with OX40 agonists and PD-L1 antagonists. Clin Cancer Res; 23(13); 3416–27. ©2017 AACR.
Synthetic Lethality Exploitation by an Anti–Trop-2-SN-38 Antibody–Drug Conjugate, IMMU-132, Plus PARP Inhibitors in BRCA1/2–wild-type Triple-Negative Breast Cancer
Authors: Cardillo Thomas M. , Sharkey Robert M. , Rossi Diane L. , Arrojo Roberto , Mostafa Ali A. , Goldenberg David M. 
Published: January 2017

Abstract
Purpose: Both PARP inhibitors (PARPi) and sacituzumab govitecan (IMMU-132) are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)–inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC.
Experimental Design: In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, double-stranded DNA (dsDNA) breaks, and cell-cycle arrest. Mice bearing BRCA1/2-mutated or –wild-type human TNBC tumor xenografts were treated with the combination of IMMU-132 and PARPi (olaparib or talazoparib). Study survival endpoint was tumor progression to &gt;1.0 cm3 and tolerability assessed by hematologic changes.
Results: Combining IMMU-132 in TNBC with all three different PARPi results in synergistic growth inhibition, increased dsDNA breaks, and accumulation of cells in the S-phase of the cell cycle, regardless of BRCA1/2 status. A combination of IMMU-132 plus olaparib or talazoparib produces significantly improved antitumor effects and delay in time-to-tumor progression compared with monotherapy in mice bearing BRCA1/2-mutated HCC1806 TNBC tumors. Furthermore, in mice bearing BRCA1/2–wild-type tumors (MDA-MB-468 or MDA-MB-231), the combination of IMMU-132 plus olaparib imparts a significant antitumor effect and survival benefit above that achieved with monotherapy. Most importantly, this combination was well tolerated, with no substantial changes in hematologic parameters.
Conclusions: These data demonstrate the added benefit of combining Topo I inhibition mediated by IMMU-132 with synthetic lethality provided by PARPi in TNBC, regardless of BRCA1/2 status, thus supporting the rationale for such a combination clinically. Clin Cancer Res; 23(13); 3405–15. ©2017 AACR.
Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth
Authors: Tauro Marilena , Shay Gemma , Sansil Samer S. , Laghezza Antonio , Tortorella Paolo , Neuger Anthony M. , Soliman Hatem , Lynch Conor C. 
Published: January 2017

Abstract
Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor- or host-derived MMP-2 contributes to breast cancer growth and does so by processing substrates, including type I collagen and TGFβ latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, in vivo, MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective bisphosphonic-based MMP-2 inhibitors (BMMPIs) that allowed for specific bone targeting. In vitro, BMMPIs affected the viability of breast cancer cell lines and osteoclast precursors, but not osteoblasts. In vivo, we demonstrated using two bone metastatic models (PyMT-R221A and 4T1) that BMMPI treatment significantly reduced tumor growth and tumor-associated bone destruction. In addition, BMMPIs are superior in promoting tumor apoptosis compared with the standard-of-care bisphosphonate, zoledronate. We demonstrated MMP-2–selective inhibition in the bone microenvironment using specific and broad-spectrum MMP probes. Furthermore, compared with zoledronate, BMMPI-treated mice had significantly lower levels of TGFβ signaling and MMP-generated type I collagen carboxy-terminal fragments. Taken together, our data show the feasibility of selective inhibition of MMPs in the bone metastatic breast cancer microenvironment. We posit that BMMPIs could be easily translated to the clinical setting for the treatment of bone metastases given the well-tolerated nature of bisphosphonates. Mol Cancer Ther; 16(3); 494–505. ©2017 AACR.
Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer
Authors: Li Jie , Wang Ruixin , Kong Yifan , Broman Meaghan M. , Carlock Colin , Chen Long , Li Zhiguo , Farah Elia , Ratliff Timothy L. , Liu Xiaoqi 
Published: January 2017

Abstract
Olaparib is an FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of olaparib in 22RV1, a BRCA1-deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with olaparib results in an override of the G1–S checkpoint, leading to high expression of Plk1, which attenuates olaparib's overall efficacy. In BRCA1 wild-type C4-2 cells, Plk1 inhibition also significantly increases the efficacy of olaparib in the presence of p53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA–mutant patient subgroups who might also respond favorably to PARPi. Mol Cancer Ther; 16(3); 469–79. ©2017 AACR.
The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma
Authors: Zhang Jiyuan , Vlasevska Sofija , Wells Victoria A. , Nataraj Sarah , Holmes Antony B. , Duval Romain , Meyer Stefanie N. , Mo Tongwei , Basso Katia , Brindle Paul K. , Hussein Shafinaz , Dalla-Favera Riccardo , Pasqualucci Laura 
Published: January 2017

Abstract
Inactivating mutations of the CREBBP acetyltransferase are highly frequent in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common germinal center (GC)–derived cancers. However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Here, we show that CREBBP regulates enhancer/super-enhancer networks with central roles in GC/post-GC cell fate decisions, including genes involved in signal transduction by the B-cell receptor and CD40 receptor, transcriptional control of GC and plasma cell development, and antigen presentation. Consistently, Crebbp-deficient B cells exhibit enhanced response to mitogenic stimuli and perturbed plasma cell differentiation. Although GC-specific loss of Crebbp was insufficient to initiate malignant transformation, compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics of FL and DLBCL, develop clonal lymphomas recapitulating the features of the human diseases. These findings establish CREBBP as a haploinsufficient tumor-suppressor gene in GC B cells and provide insights into the mechanisms by which its loss contributes to lymphomagenesis.
Significance: Loss-of-function mutations of CREBBP are common and early lesions in FL and DLBCL, suggesting a prominent role in lymphoma initiation. Our studies identify the cellular program by which reduced CREBBP dosage facilitates malignant transformation, and have direct implications for targeted lymphoma therapy based on drugs affecting CREBBP-mediated chromatin acetylation. Cancer Discov; 7(3); 322–37. ©2017 AACR.
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