bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temporal and geographic patterns of stab injuries in young people: a retrospective cohort study from a UK major trauma centre
Authors: Vulliamy Paul , Faulkner Mark , Kirkwood Graham , West Anita , O’Neill Breda , Griffiths Martin P , Moore Fionna , Brohi Karim 
Published: November 2018

ObjectivesTo describe the epidemiology of assaults resulting in stab injuries among young people. We hypothesised that there are specific patterns and risk factors for injury in different age groups.DesignEleven-year retrospective cohort study.SettingUrban major trauma centre in the UK.Participants1824 patients under the age of 25 years presenting to hospital after a stab injury resulting from assault.OutcomesIncident timings and locations were obtained from ambulance service records and triangulated with prospectively collected demographic and injury characteristics recorded in our hospital trauma registry. We used geospatial mapping of individual incidents to investigate the relationships between demographic characteristics and incident timing and location.ResultsThe majority of stabbings occurred in males from deprived communities, with a sharp increase in incidence between the ages of 14 and 18 years. With increasing age, injuries occurred progressively later in the day (r2=0.66, p<0.01) and were less frequent within 5 km of home (r2=0.59, p<0.01). Among children (age <16), a significant peak in injuries occurred between 16:00 and 18:00 hours, accounting for 22% (38/172) of injuries in this group compared with 11% (182/1652) of injuries in young adults. In children, stabbings occurred earlier on school days (hours from 08:00: 11.1 vs non-school day 13.7, p<0.01) and a greater proportion were within 5 km of home (90% vs non-school day 74%, p=0.02). Mapping individual incidents demonstrated that the spike in frequency in the late afternoon and early evening was attributable to incidents occurring on school days and close to home.ConclusionsAge, gender and deprivation status are potent influences on the risk of violent injury in young people. Stab injuries occur in characteristic temporal and geographical patterns according to age group, with the immediate after-school period associated with a spike in incident frequency in children. This represents an opportunity for targeted prevention strategies in this population.
Prevalence and patterns of multimorbidity in Amazon Region of Brazil and associated determinants: a cross-sectional study
Authors: Araujo Maria Elizete A , Silva Marcus T , Galvao Tais F , Nunes Bruno P , Pereira Mauricio G 
Published: November 2018

ObjectivesTo estimate the prevalence of multimorbidity and to identify factors associated with it in the adult population from the metropolitan region of Manaus.DesignCross-sectional population-based study.SettingInterviews conducted between May and August of 2015 in eight cities that compose the metropolitan region of Manaus, Amazonas, Brazil.Participants4001 adults aged ≥18 years.Primary outcome measuresMultimorbidity, measured by the occurrence of ≥2 and ≥3 chronic diseases, was the primary outcome. The associated factors were investigated by calculating the prevalence ratio (PR) obtained by Poisson regression, with robust adjustment of the variance in a hierarchical model. A factor analysis was conducted to investigate multimorbidity clusters.ResultsHalf of the interviewees were women. The presence of a chronic disease was reported by 57.2% (95% CI 56.6% to 59.7%) of the interviewees, and the mean morbidity was 1.2 (1.1–1.2); 29.0% (95% CI 27.6% to 30.5%) reported ≥2 morbidities and 15.2% (95% CI 14.1% to 16.4%) reported ≥3 chronic conditions. Back pain was reported by one-third of the interviewees. Multimorbidity was highest in women, PR=1.66 (95% CI 1.50 to 1.83); the elderly, PR=5.68 (95% CI 4.51 to 7.15) and individuals with worse health perception, PR=3.70 (95% CI 2.73 to 5.00). Associated factors also included undergoing medical consultations, hospitalisation in the last year, suffering from dengue in the last year and seeking the same healthcare service. Factor analysis revealed a pattern of multimorbidity in women. The factor loading the most strength of association in women was heart disease. In men, an association was identified in two groups, and lung disease was the disease with the highest factorial loading.ConclusionMultimorbidity was frequent in the metropolitan region of Manaus. It occurred most often in women, in the elderly and in those with worse health perception.
A randomised placebo-controlled double-blind multicentre trial comparing antibiotic therapy with placebo in the treatment of uncomplicated acute appendicitis: APPAC III trial study protocol
Authors: Sippola Suvi , Grönroos Juha , Sallinen Ville , Rautio Tero , Nordström Pia , Rantanen Tuomo , Hurme Saija , Leppäniemi Ari , Meriläinen Sanna , Laukkarinen Johanna , Savolainen Heini , Virtanen Johanna , Salminen Paulina 
Published: November 2018

IntroductionRecent studies show that antibiotic therapy is safe and feasible for CT-confirmed uncomplicated acute appendicitis. Spontaneous resolution of acute appendicitis has already been observed over a hundred years ago. In CT-confirmed uncomplicated acute diverticulitis (left-sided appendicitis), studies have shown no benefit from antibiotics compared with symptomatic treatment, but this shift from antibiotics to symptomatic treatment has not yet been widely implemented in clinical practice. Recently, symptomatic treatment of uncomplicated acute appendicitis has been demonstrated in a Korean open-label study. However, a double-blinded placebo-controlled study to illustrate the role of antibiotics and spontaneous resolution of uncomplicated acute appendicitis is still lacking.Methods and analysisThe APPAC III (APPendicitis ACuta III) trial is a multicentre, double-blind, placebo-controlled, superiority randomised study comparing antibiotic therapy with placebo in the treatment CT scan-confirmed uncomplicated acute appendicitis aiming to evaluate the role of antibiotics in the resolution of uncomplicated acute appendicitis. Adult patients (18–60 years) with CT scan-confirmed uncomplicated acute appendicitis (the absence of appendicolith, abscess, perforation and tumour) will be enrolled in five Finnish university hospitals.Primary endpoint is success of the randomised treatment, defined as resolution of acute appendicitis resulting in discharge from the hospital without surgical intervention within 10 days after initiating randomised treatment (treatment efficacy). Secondary endpoints include postintervention complications, recurrent symptoms after treatment up to 1 year, late recurrence of acute appendicitis after 1 year, duration of hospital stay, sick leave, treatment costs and quality of life. A decrease of 15 percentage points in success rate is considered clinically important difference. The superiority of antibiotic treatment compared with placebo will be analysed using Fisher’s one-sided test and CI will be calculated for proportion difference.Ethics and disseminationThis protocol has been approved by the Ethics Committee of Turku University Hospital and the Finnish Medicines Agency (FIMEA). The findings will be disseminated in peer-reviewed academic journals.Trial registration numberNCT03234296; Pre-results.
Patients’ attendance patterns to different healthcare settings and perceptions of stakeholders regarding screening for chronic, non-communicable diseases in high street dental practices and community pharmacy: a cross-sectional study
Authors: Yonel Zehra , Sharma Praveen , Yahyouche Asma , Jalal Zahraa , Dietrich Thomas , Chapple Iain L 
Published: November 2018

ObjectiveNon-communicable diseases (NCDs) impose a significant health and economic burden. This study aimed to assess the differential attendance patterns of public to different healthcare professionals and gauge the opinions of key stakeholders towards screening of NCDs by allied healthcare professionals.DesignQuestionnaires were designed piloted and subsequently completed by key stakeholders. The results were analysed descriptively.SettingPublic questionnaires were undertaken in a West Midlands transport station and Public Markets. High street dental and community pharmacy settings were selected via local clinical and research networks. Healthcare professionals were identified using professional networks and were emailed a web link to an online survey.Participants1371 members of the public, 1548 patients and 222 healthcare professionals (doctors general practitioner (GP), dentists general dental practitioner (GDP) and pharmacists) completed the questionnaires.Outcome measuresThe outcome was to compare attendance patterns at GDP and GP practices to determine whether different populations were more likely to access different healthcare professionals, this included determining when patients were last screened for NCDs by their GP. Additionally, the willingness of patients to undergo the required intervention and the opinions of stakeholders regarding the concept of screening for the specified NCDs in general dental and community pharmacy settings were also explored.Results12% of patients who reported seeing a GDP biannually reported that they had not had contact with a GP in the last year. Over 61% of the public reported attending a GDP biannually, of this group 48% reported having never had a check-up at the GP. All stakeholders surveyed were in broad support of the concept of allied health professionals undertaking screening for specific general health conditions.ConclusionsThis study has established that allied healthcare professionals may have access to different cohorts of the population to GPs. If GDPs and pharmacists have access to patients who are not using healthcare services elsewhere, they may be ideally placed to risk assess, and where appropriate offer preventative advice and test for NCDs.
Tacrolimus in non-Asian patients with SLE: a real-life experience from three European centres
Authors: Tani Chiara , Elefante Elena , Martin-Cascón Miguel , Belhocine Meriem , Lavilla Olleros Cristina , Vagelli Roberta , Stagnaro Chiara , Costedoat-Chalumeau Nathalie , Ruiz-Irastorza Guillermo , Mosca Marta 
Published: November 2018

ObjectivesTo analyse the real-life practice on the use of Tacrolimus (TAC) in patients with systemic lupus erythematosus (SLE) from three European SLE referral centres.MethodsAdult patients with SLE regularly followed at three European referral centres were included. Demographics, cumulative organ involvement, treatment history, Systemic Lupus Disease Activity Index (SLEDAI), laboratory features and physician’s judgement were collected at baseline and at 3–6–12 months after starting TAC.Results29 patients were included (89% female, mean age 38±9 years). Ethnicity was predominantly Caucasian (82%), Black African (11%), Hispanic (3.5%) and Caribbean (3.5%). The main indications for TAC prescription were renal involvement (82.7%), arthritis (10.3%), cutaneous manifestations (6.8%), haematological manifestations (6.8%), serositis (3.4%). At 3 months, there was a clinical improvement in 21 patients (72.4%) and 9 of these experienced a complete resolution of symptoms (31%). This corresponds to: (1) a significant decrease in the mean SLEDAI; (2) a significant decrease in the mean 24  hours proteinuria; a significant increase in C3 and stable creatinine values. At 6 months (n=25), the physician declared an improvement in 19 patients (76%) and a complete resolution of symptoms in 9 (36%). The same trend was observed at 12 months of follow-up. TAC was discontinued in nine pts (31%); reasons for discontinuation were inefficacy (13.8%), drug intolerance (10%) and disease remission (6.9%).ConclusionsDespite the limitation due to the small number of patients and the uncontrolled nature of the study, these data show that TAC can be considered a valid therapeutic option in patients with SLE, especially for renal involvement.
Predictors of persistent disease activity and long quiescence in systemic lupus erythematosus: results from the Hopkins Lupus Cohort
Authors: Giannakou Ioanna , Chatzidionysiou Katerina , Magder Laurence S , Györi Noemi , van Vollenhoven Ronald , Petri Michelle A 
Published: November 2018

ObjectivesThe aim of this study is to identify prognostic factors of persistent disease activity and long quiescence in systemic lupus erythematosus (SLE).MethodsPatients enrolled in the Hopkins Lupus Cohort from 1987 to 2012, who attended at least three visits per year during 3 consecutive years following baseline and had available information on disease activity were included. Patterns of SLE disease activity over the 3-year period were defined as: persistent long quiescent (pLQ), persistent relapsing-remitting (pRR), persistent chronic active (pCA) and mixed based on Modified SLE Disease Activity Index (M-SLEDAI). Possible predictors of pCA (vs pLQ, pRR and mixed) and pLQ (vs pCA, pRR and mixed) were identified by univariate and multivariate logistic regression analyses.Results916 patients were included. In the multivariate analysis, use of hydroxychloroquine (OR: 0.45, 95%  CI 0.22 to 0.92, p=0.03), African American ethnicity (OR: 2.36, 95%  CI 1.15 to 4.85, p=0.02) and baseline SLEDAI (OR: 1.10, 95%  CI 1.03 to 1.17, p=0.005) remained significant predictors of pCA. Higher education (>12 years; OR. 2.07, 95%  CI 1.07 to 4.03, p=0.03) and lower baseline SLEDAI (OR: 0.67, 95%  CI 0.56 to 0.82, p<0.001) were significant predictors of pLQ, while African American (OR: 0.38, 95%  CI 0.17 to 0.83, p=0.02) and female patients (OR: 0.26, 95%  CI 0.12 to 0.57, p<0.001) were less likely to achieve pLQ.ConclusionAfrican American ethnicity and high disease activity at baseline predict chronic activity in SLE, regardless of treatment, years of education and income. Higher education, low disease activity at baseline and male sex predict long quiescence. The use of hydroxychloroquine is independently associated with a lower risk of chronically active disease.
EGFR Cooperates with EGFRvIII to Recruit Macrophages in Glioblastoma
Authors: An Zhenyi , Knobbe-Thomsen Christiane B. , Wan Xiaohua , Fan Qi Wen , Reifenberger Guido , Weiss William A. 
Published: November 2018

Abstract

Amplification of the EGFR gene and its truncation mutant EGFRvIII are hallmarks of glioblastoma. Although coexpression of EGFR and EGFRvIII confers a growth advantage, how EGFR and EGFRvIII influence the tumor microenvironment remains incompletely understood. Here, we show that EGFR and EGFRvIII cooperate to induce macrophage infiltration via upregulation of the chemokine CCL2. EGFRvIII was significantly enriched in glioblastoma patient samples with high CCL2, and knockout of CCL2 in tumors coexpressing EGFR and EGFRvIII led to decreased infiltration of macrophages. KRAS was a critical signaling intermediate for EGFR- and EGFRvIII-induced expression of CCL2. Our results illustrate how EGFR and EGFRvIII direct the microenvironment in glioblastoma.

Significance:
Full-length EGFR and truncated EGFRvIII work through KRAS to upregulate the chemokine CCL2 and drive macrophage infiltration in glioblastoma.
Assessment of Tumor Redox Status through (S)-4-(3-[18F]fluoropropyl)-L-Glutamic Acid PET Imaging of System xc− Activity
Authors: McCormick Patrick N. , Greenwood Hannah E. , Glaser Matthias , Maddocks Oliver D.K. , Gendron Thibault , Sander Kerstin , Gowrishankar Gayatri , Hoehne Aileen , Zhang Tong , Shuhendler Adam J. , Lewis David Y. , Berndt Mathias , Koglin Norman , Lythgoe Mark F. , Gambhir Sanjiv S. , Årstad Erik , Witney Timothy H. 
Published: November 2018

Abstract

The cell's endogenous antioxidant system is vital to maintain redox homeostasis. Despite its central role in normal and pathophysiology, no noninvasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc− maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here, we show that tumor cell retention of a system xc−-specific PET radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment.

Significance:
[18F]FSPG PET imaging provides a sensitive noninvasive measure of tumor redox status and provides an early marker of tumor response to therapy.
See related commentary by Lee et al., p. 701
High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer
Authors: Garinet Simon , Pignot Géraldine , Vacher Sophie , Le Goux Constance , Schnitzler Anne , Chemlali Walid , Sirab Nanor , Barry Delongchamps Nicolas , Zerbib Marc , Sibony Mathilde , Allory Yves , Damotte Diane , Bieche Ivan 
Published: November 2018

Abstract

Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, noncoding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of GPR126 gene in 2.7% of a large breast cancer series. As GPR126 is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 nonmuscle-invasive bladder cancers (NMIBC) and 59 muscle-invasive bladder cancers (MIBC). GPR126 mutations were analyzed by high-resolution melting and Sanger sequencing, and GPR126 expression levels were assessed using real-time quantitative RT-PCR. In NMIBC, somatic GPR126 noncoding mutations occurred in 47.7% of samples and were negatively associated with GPR126 mRNA levels. GPR126 mutations had higher frequencies in nonsmoker patients and were associated with a prior history of NMIBC. GPR126 overexpression was detected in 70.5% of samples. GPR126 mutation and overexpression status were not associated with outcome. In MIBC, somatic GPR126 mutations occurred in 44.1% of samples. Mutations were more frequent in females. GPR126 overexpression was detected in 27.1% of the sample. A trend toward significance was observed between GPR126 overexpression and better outcome. We identified the second most frequent mutational hotspot after TERT promoter (∼70%) in bladder cancer, with a mutation rate of approximately 50%.

Implications:
The GPR126 intronic mutational hotspot could be a promising clinical biomarker candidate to monitor tumor burden using circulating tumor DNA in bladder cancer.
Molecular Correlates of Metastasis by Systematic Pan-Cancer Analysis Across The Cancer Genome Atlas
Authors: Chen Fengju , Zhang Yiqun , Varambally Sooryanarayana , Creighton Chad J. 
Published: November 2018

Abstract

Tumor metastasis is a major contributor to mortality of cancer patients, but the process remains poorly understood. Molecular comparisons between primary tumors and metastases can provide insights into the pathways and processes involved. Here, we systematically analyzed and cataloged molecular correlates of metastasis using The Cancer Genome Atlas (TCGA) datasets across 11 different cancer types, these data involving 4,473 primary tumor samples and 395 tumor metastasis samples (including 369 from melanoma). For each cancer type, widespread differences in gene transcription between primary and metastasis samples were observed. For several cancer types, metastasis-associated genes from TCGA comparisons were found to overlap extensively with external results from independent profiling datasets of metastatic tumors. Although some differential expression patterns associated with metastasis were found to be shared across multiple cancer types, by and large each cancer type showed a metastasis signature that was distinctive from those of the other cancer types. Functional categories of genes enriched in multiple cancer type–specific metastatic overexpression signatures included cellular response to stress, DNA repair, oxidation–reduction process, protein deubiquitination, and receptor activity. The TCGA-derived prostate cancer metastasis signature in particular could define a subset of aggressive primary prostate cancer. Transglutaminase 2 protein and mRNA were both elevated in metastases from breast and melanoma cancers. Alterations in miRNAs and in DNA methylation were also identified.

Implications:
Our findings suggest that there are different molecular pathways to metastasis involved in different cancers. Our catalog of alterations provides a resource for future studies investigating the role of specific genes in metastasis.
Nuclear E-Cadherin Acetylation Promotes Colorectal Tumorigenesis via Enhancing β-Catenin Activity
Authors: Zhao Yongxu , Yu Tao , Zhang Nan , Chen Jianxia , Zhang Peng , Li Shuang , Luo Lijun , Cui Zhenling , Qin Yue , Liu Feng 
Published: November 2018

Abstract

The E-cadherin/β-catenin signaling pathway plays a critical role in the maintenance of epithelial architecture and regulation of tumor progression. Normally, E-cadherin locates on the cell surface with its cytosolic domain linking to the actin cytoskeleton through interaction with catenins. Although the nuclear localization of E-cadherin has been frequently observed in various types of cancers, little is known regarding the functional consequences of its nuclear translocation. Here, we showed that in colorectal cancer samples and cell lines, E-cadherin localized in the nucleus; and the nuclear localization was mediated through protein interaction with CTNND1. In the nucleus, E-cadherin was acetylated by CREB-binding protein at Lysine870 and Lysine871 in its β-catenin–binding domain, and the acetylation can be reversed by SIRT2. Acetylation of nuclear E-cadherin attenuated its interaction with β-catenin, which therefore released β-catenin from the complex, resulting in increased expression of its downstream genes and accelerated tumor growth and migration. Further study showed that acetylation level of nuclear E-cadherin had high prognostic significance in clinical colorectal samples. Taken together, our findings reveal a novel mechanism of tumor progression through posttranslational modification of E-cadherin, which may serve as a potential drug target of tumor therapy.

Implications:
This finding that acetylation of nuclear E-cadherin regulates β-catenin activity expands our understanding of the acetylation of E-cadherin promotes colorectal cancer cell growth and suggests novel therapeutic approaches of targeting acetylation in tumors.
A New Regression-Based Tail Index Estimator
Authors: Nicolau João , Rodrigues Paulo M. M. 
Published: November 2018

Abstract
A new regression-based approach for the estimation of the tail index of heavy-tailed distributions with several important properties is introduced. First, it provides a bias reduction when compared to available regression-based methods; second, it is resilient to the choice of the tail length used for the estimation of the tail index; third, when the effect of the slowly varying function at infinity of the Pareto distribution vanishes slowly, it continues to perform satisfactorily; and fourth, it performs well under dependence of unknown form. An approach to compute the asymptotic variance under time dependence and conditional heteroskcedasticity is also provided.