bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of weight status in the response to Step-2 maintenance therapies in children with asthma
Authors: Longo Cristina , Bartlett Gillian , Schuster Tibor , Ducharme Francine M. , MacGibbon Brenda , Barnett Tracie A. 
Published: April 2019

IntroductionOverweight children with asthma may display impaired response to inhaled corticosteroids (ICS), possibly due to non-eosinophilic inflammation or weight-related lung compression; these mechanisms may differentially affect response to ICS and leukotriene receptor antagonists (LTRAs). We assessed whether weight status modified the response to low-dose ICS and LTRA Step-2 monotherapy.MethodsA historical cohort study from clinical data linked to administrative databases was conducted among children aged 2–18 years with specialist-diagnosed asthma who were initiating or continuing a Step-2 monotherapy from 2000 to 2007 at the Montreal Children’s Hospital Asthma Centre. The outcome was time-to-management failure defined as any step-up in therapy, acute care visit, hospitalisation or oral corticosteroids for asthma, whichever occurred first. The independent and joint effects of weight status (body mass index [BMI] percentile) and time-varying treatment on time-to-management failure were estimated with marginal structural Cox models. The likelihood ratio test (LRT) and relative excess risk due to interaction (RERI) were computed to assess treatment effect modification by weight status on the multiplicative and additive scales.ResultsOf the 433 and 85 visits with a low-dose ICS and LTRA prescription, respectively, 388 management failures occurred over 14 529 visit-weeks of follow-up. Children using LTRA compared with low-dose ICS tended to have an overall higher risk of early management failure (HR 1.52; 95% CI 0.72 to 3.22). Irrespective of treatment, the hazard of management failure increased by 5% (HR 1.05; 95% CI 1.01 to 1.10) for every 10-unit increase in BMI percentile. An additional hazard reduction of 17% (HR 0.83; 95% CI 0.70 to 0.99) was observed for every 10-unit increase in BMI percentile among LTRA users, but not for ICS (HR 0.95; 95% CI 0.86 to 1.04). The LRT indicated a departure from exact multiplicativity (p<0.0001), and the RERIs for ICS and LTRA were −0.05 (95% CI −0.14 to 0.05) and −0.52 (95% CI −1.76 to 0.71).ConclusionsWeight status was associated with earlier time-to-management failure in children prescribed Step-2 therapy. This hypothesis-generating study suggests that LTRA response increases in children with higher BMI percentiles, although further research is warranted to confirm findings.
Randomised Ambulatory Management of Primary Pneumothorax (RAMPP): protocol of an open-label, randomised controlled trial
Authors: Hallifax Rob , Laskawiec-Szkonter Magda , Dobson Melissa , Gerry Stephen , Miller Robert F , Harvey John E , Rahman Najib 
Published: April 2019

IntroductionPneumothorax is a common clinical problem. Primary spontaneous pneumothorax (PSP) occurs in otherwise fit young patients, but optimal management is not clearly defined and often results in a long hospital stay. Ambulatory treatment options are available, but the existing data on their efficacy are poor. The Randomised Ambulatory Management of Primary Pneumothorax trial is a multicentre, randomised controlled trial comparing ambulatory management with standard care, specifically designed to safely and effectively reduce hospital stay.Methods and analysis236 patients with PSP will be recruited from UK hospitals. Patients will be randomised 1:1 to treatment to either the ‘Intervention’ arm (ambulatory device; Rocket Pleural Vent) or the ‘Control’ arm (aspiration ± standard chest drain insertion). Patients will be followed up for a total of 12 months to assess recurrence rates. The primary outcome is total length of stay in hospital (including readmissions) up to 30 days postrandomisation. The secondary outcomes are pain and breathlessness scores, air leak measurement and radiological evidence (on CT scanning) of emphysema-like changes, compared with short-term and long-term outcomes, respectively, and health economic analysis.Ethics and disseminationThe trial has received ethical approval from the National Research Ethics Service Committee South-Central Oxford A (15/SC/0240).Trial registration numberISRCTN79151659
Deleterious somatic variants in 473 consecutive individuals with ovarian cancer: results of the observational AGO-TR1 study (NCT02222883)
Authors: Hauke Jan , Hahnen Eric , Schneider Stephanie , Reuss Alexander , Richters Lisa , Kommoss Stefan , Heimbach André , Marmé Frederik , Schmidt Sandra , Prieske Katharina , Gevensleben Heidrun , Burges Alexander , Borde Julika , De Gregorio Nikolaus , Nürnberg Peter , El-Balat Ahmed , Thiele Holger , Hilpert Felix , Altmüller Janine , Meier Werner , Dietrich Dimo , Kimmig Rainer , Schoemig-Markiefka Birgid , Kast Karin , Braicu Elena , Baumann Klaus , Jackisch Christian , Park-Simon Tjoung-Won , Ernst Corinna , Hanker Lars , Pfisterer Jacobus , Schnelzer Andreas , du Bois Andreas , Schmutzler Rita K , Harter Philipp 
Published: April 2019

BackgroundFor individuals with ovarian cancer (OC), therapy options mainly depend on BRCA1/2 germline status. What is the prevalence of deleterious somatic variants, that is, does genetic tumour testing identify subgroups of individuals who also might benefit from targeted therapy?MethodsPaired analysis of tumour-derived versus blood-derived DNA to determine the prevalence of deleterious somatic variants in OC predisposition genes (ATM, BRCA1/2, BRIP1, MSH2/6, PALB2, RAD51C/D and TP53) and the PIK3CA and PTEN genes in individuals with OC (AGO-TR1 study, NCT02222883). Results were complemented by BRCA1, PALB2 and RAD51C promoter methylation analyses and stratified by histological subtype; 473 individuals were included.ResultsThe combined analyses revealed that deleterious germline variants in established OC predisposition genes (all: 125/473, 26.4%; BRCA1/2: 97/473, 20.5%), deleterious somatic variants in established OC predisposition genes excluding TP53 (all: 39/473, 8.2%; BRCA1/2: 30/473, 6.3%) and promoter methylation (all: 67/473, 14.2%; BRCA1: 57/473, 12.1%; RAD51C: 10/473, 2.1%; PALB2: 0/473) were mutually exclusive, with a few exceptions. The same holds true for deleterious somatic PIK3CA and/or PTEN variants (33/473, 7.0%) found to be enriched in endometrioid and clear cell OC (16/35, 45.7%); 84.3 % of the deleterious single-nucleotide/indel germline variants in established OC predisposition genes showed significantly higher variant fractions (VFs) in the tumour-derived versus blood-derived DNA, indicating a loss of the wild-type alleles.ConclusionTumour sequencing of the BRCA1, BRCA2, PIK3CA and PTEN genes along with BRCA1 and RAD51C promoter methylation analyses identified large subgroups of germline mutation-negative individuals who may be addressed in interventional studies using PARP or PI3K/AKT/mTOR inhibitors.Trial registration numberNCT02222883
Injuries associated with long working hours among employees in the US mining industry: risk factors and adverse outcomes
Authors: Friedman Lee S , Almberg Kirsten S , Cohen Robert A 
Published: April 2019

ObjectivesThe mining industry is increasingly adopting extended workdays of 10–12 hour shifts. Studies demonstrate that long work hours are associated with psychomotor impairments caused by fatigue and an increased risk of injury. However, studies involving miners remain limited. This analysis aimed to identify risk factors associated with long working hour injuries and to determine if long working hour incidents were associated with being killed or incidents involving multiple injured workers.MethodsData from US Mine Safety and Health Administration Part 50 reports, 1983–2015, were used to identify long working hour injuries, which were defined as incidents occurring nine or more hours after the start of a shift.ResultsA total of 52 206 injuries (9.6%) occurred during long working hours. The proportion of long working hour injuries increased from 5.5% of all injuries in 1983 to its peak in 2015 at 13.9% (p<0.001). Risk factors associated with long working hour injuries included irregular shift starts, being newly employed, employment by a contractor, metal/non-metal operations and mines with <100 employees. In two separate adjusted models, long working hour injuries were associated with a higher odds of death (adjusted OR [aOR]=1.32; 95% CI 1.18 to 1.48) and single incidents resulting in two or more workers injured (aOR=1.73; 95% CI 1.58 to 1.89).ConclusionsLong working hour injuries were associated with a lack of routine, being new at the mine and specific mining activities. An international shift towards using contract labour and extended workdays indicates that injuries during long working hours will likely continue to grow as a problem in the mining industry.
A zero coronary artery calcium score in patients with stable chest pain is associated with a good prognosis, despite risk of non-calcified plaques
Authors: Wang Xue , Le Elizabeth Phuong Vi , Rajani Nikil K , Hudson-Peacock NJ , Pavey Holly , Tarkin Jason M , Babar Judith , Williams Michelle Claire , Gopalan Deepa , Rudd James H F 
Published: April 2019

ObjectivesTo estimate the prevalence of non-calcified coronary artery disease (CAD) in patients with suspected stable angina and a zero coronary artery calcification (CAC) score, and to assess the prognostic significance of a zero CAC in these symptomatic patients.MethodsIn this prospective cohort study, consecutive patients with stable chest pain underwent CAC scoring ± CT coronary angiography (CTCA) as part of routine clinical care at a single tertiary centre over 7 years. Major adverse cardiac event (MACE) was defined as cardiac death, non-fatal myocardial infarction and/or non-elective revascularisation.ResultsA total of 915 of 1753 (52.2%) patients (mean age 56.8 ± 12.0 years; 46.2% male) had a zero CAC score. Of the 751 (82.1%) patients with a zero CAC in whom CTCA was performed, 674 (89.7%) had normal coronary arteries, 63 (8.4%) had non-calcified CAD with < 50% stenosis and 14 (1.9%) had ≥ 50% stenosis in at least one coronary artery. The negative predictive value of a zero CAC for excluding a ≥ 50% CTCA stenosis was 98.1%. Over a median follow-up period of 2.2 years (range 1.0–7.0 years), the absolute annualised rates of MACE were as follows: zero CAC 1.9 per 1000 person-years and non-zero CAC 7.4 per 1000 person-years (HR 3.8, p = 0.009). However, after adjusting for age, gender and cardiovascular risk factors using a multivariable Cox proportional hazards model, there was no statistically significant difference in the risk of MACE between the two patient cohorts (p = 0.19). After adjusting for age, gender and cardiovascular risk factors, the HR for all-cause mortality among the zero CAC cohort vers non-zero CAC was 2.1 (p = 0.27).ConclusionA zero CAC score in patients undergoing CT scanning for suspected stable angina has a high negative predictive value for the exclusion of obstructive CAD and is associated with a good medium-term prognosis.
Curcumin Promotes Connexin 43 Degradation and Temozolomide-Induced Apoptosis in Glioblastoma Cells
Authors: Huang Bor-Ren , Tsai Chon-Haw , Chen Chun-Chuan , Way Tzong-Der , Kao Jung-Yie , Liu Yu-Shu , Lin Hsiao-Yun , Lai Sheng-Wei , Lu Dah-Yuu 
Published: April 2019

Glioblastoma (GBM) is the most commonly occurring tumor in the cerebral hemispheres. Currently, temozolomide (TMZ), an alkylating agent that induces DNA strand breaks, is considered the frontline chemotherapeutic agent for GBM. Despite its frontline status, GBM patients commonly exhibit resistance to TMZ treatment. We have recently established and characterized TMZ-resistant human glioma cells. The aim of this study is to investigate whether curcumin modulates cell apoptosis through the alternation of the connexin 43 (Cx43) protein level in TMZ-resistant GBM. Overexpression of Cx43, but not ATP-binding cassette transporters (ABC transporters), was observed (approximately 2.2-fold) in TMZ-resistant GBM cells compared to the Cx43 levels in parental GBM cells. Furthermore, at a concentration of 10[Formula: see text][Formula: see text]M, curcumin significantly reduced Cx43 protein expression by about 40%. In addition, curcumin did not affect the expression of other connexins like Cx26 or epithelial-to-mesenchymal transition (EMT) proteins such as [Formula: see text]-catenin or [Formula: see text]E-catenin. Curcumin treatment led to an increase in TMZ-induced cell apoptosis from 4% to 8%. Importantly, it did not affect the mRNA expression level of Cx43. Concomitant treatment with the translation inhibitor cycloheximide (CHX) exerted additional effects on Cx43 degradation. Treatment with the autophagy inhibitor 3-MA (methyladenine) did not affect the curcumin-induced Cx43 degradation. Interestingly, treatment with the proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) significantly negated the curcumin-induced Cx43 degradation, which suggests that curcumin-induced Cx43 degradation occurs through the ubiquitin-proteasome pathway.
Evaluation of carrier lifetime and photocatalytic properties of annealed ZnS/TiO2 nanocomposite
Authors: Ohara Tomoya , Furube Akihiro , Koinkar Pankaj , Patil Deepak 
Published: April 2019

In this study, zinc sulfide (ZnS)/titanium oxide(TiO2) nanoparticles were prepared by a two-step facile hydrothermal method and then annealing at [Formula: see text] for 30 min. Also, the transient absorption measurement and photocatalytic activity of ZnS/TiO2 before and after annealing were investigated. The characterization technique such as the scanning electron microscopy (SEM) and X-ray diffraction (XRD) and UV–Visible spectroscopy have been employed to study the surface morphology and structural details. The SEM image shows the change in the surface morphology due to annealing. The change of the crystal structure of ZnS–TiO2 is revealed by XRD spectra. The femtosecond transient absorption measurement showed moderate decay over several hundred picoseconds for annealed ZnS/TiO2. Moreover, improved photocatalytic activity of annealed ZnS/TiO2 nanoparticles in visible light has been observed.
Effects of high-intensity interval training on microvascular glycocalyx and associated microRNAs
Authors: Schmitz Boris , Niehues Hannah , Lenders Malte , Thorwesten Lothar , Klose Andreas , Krüger Michael , Brand Eva , Brand Stefan-Martin 
Published: April 2019

High-intensity interval training (HIIT) has been proposed to exert vasculoprotective effects. This study aimed to evaluate whether HIIT affects the microvasculature, including the endothelial glycocalyx barrier, and to identify associated microRNAs (miRNAs). Fifty healthy participants (23.1 ± 3.0 yr) performed a 4-wk 4 × 30-s all-out running HIIT. Sidestream dark-field imaging was performed at baseline and follow-up to detect changes of the sublingual microvasculature including the endothelial glycocalyx. Exercise parameters were determined by continuous running field test and documentation of high-intensity runs. miRNAs potentially associated with glycocalyx thickness were selected by structured literature search and blood samples for miRNA, and lactate measurements were drawn at baseline and follow-up HIIT. At baseline, a correlation between maximal exercise performance capacity and glycocalyx thickness (determined by perfused boundary region) was detected ( P = 0.045, r = 0.303). Increased exercise performance at follow-up also correlated with glycocalyx thickness ( P = 0.031, r = 0.416), and increased high-intensity sprinting speed was associated with an increased number of perfused vessels ( P = 0.0129, r = 0.449). Literature search identified miR-143, -96-5p, and -24, which were upregulated by HIIT already at baseline and showed an association with peak blood lactate levels after sprints (all P < 0.05). Moreover, increased baseline miR-143 levels predicted increased glycocalyx thickness at follow-up (AUCmiR-143 = 0.92, 95% confidence interval, 0.81–1.0, P = 0.0008). Elevated resting miR-126 levels after the intervention were associated with cell-free versican mRNA levels. We conclude that HIIT induces changes in the endothelial glycocalyx of the microvasculature. Associated miRNAs such as miR-143 may represent a tool for monitoring early vasculoprotective adaptations to physical activity.NEW & NOTEWORTHY High-intensity interval training is known to improve health-related fitness in general and in lifestyle-induced chronic diseases. To visualize microvasculature structure and to detect exercise-induced changes, sublingual sidestream dark-field imaging microscopy was used, and circulating miRNAs were measured. This study shows that exercise-induced changes correlate with associated circulating miRNA, which might be useful for monitoring vasculoprotective effects. Furthermore, sidestream dark-field imaging may represent a sensitive tool for the early detection of exercise-induced systemic vascular changes.
Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor–engineered T Cells
Authors: Drent Esther , Poels Renée , Ruiter Ruud , van de Donk Niels W.C.J. , Zweegman Sonja , Yuan Huipin , de Bruijn Joost , Sadelain Michel , Lokhorst Henk M. , Groen Richard W.J. , Mutis Tuna , Themeli Maria 
Published: April 2019

Abstract

Purpose:
Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possible detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CAR-T) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target binding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of low-affinity CAR-T cells.

Experimental Design:
We used a series of single-chain variable fragments (scFv) with five different affinities targeting the same epitope of the multiple myeloma–associated CD38 antigen. The scFvs were incorporated in three different CAR costimulation designs and we evaluated the antitumor functionality and off-tumor toxicity of the generated CAR-T cells in vitro and in vivo.

Results:
We show that the inferior cytotoxicity and cytokine secretion mediated by CD38 CARs of very low–affinity (Kd &lt; 1.9 × 10−6 mol/L) bearing a 4-1BB intracellular domain can be significantly improved when a CD28 costimulatory domain is used. Additional 4-1BB signaling mediated by the coexpression of 4-1BBL provided the CD28-based CD38 CAR-T cells with superior proliferative capacity, preservation of a central memory phenotype, and significantly improved in vivo antitumor function, while preserving their ability to discriminate target antigen density.

Conclusions:
A combinatorial costimulatory design allows the use of very low–affinity binding domains (Kd &lt; 1 μmol/L) for the construction of safe but also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered by selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs.
Evaluating the Accuracy of the Endoscopic ABC Classification System in Diagnosing Helicobacter pylori-Infected Gastritis
Authors: Inui Masayuki , Ohwada Susumu , Inui Yoshikatsu , Kondo Yuko , Moro Amika , Sasaki Kazunari 
Published: April 2019

Aims: Evaluating the accuracy of the modified Endoscopic ABC (Endo ABC) classification with an electronic endoscopy with narrow band imaging without magnification in diagnosing Helicobacter pylori (H. pylori)-infected gastritis. Methods: A total of 576 patients were enrolled and they underwent modified Endo ABC. They were stratified into 5 groups (A to E) based on the grades of endoscopic findings. H. pylori-infected gastritis status was determined in the following ways: current H. pylori gastritis was defined as active gastritis and/or chronic atrophic gastritis (CAG) seen on endoscopy and positive H. pylori test, naïve H. pylori gastritis was defined as regular arrangement of collecting venules in the angle of the lesser curvature without CAG and negative H. pylori test, and previous H. pylori gastritis was defined as negative H. pylori tests regardless of the presence of CAG. Results: Endo A has 97% accuracy and 100% positive predictive value in diagnosing naïve H. pylori gastritis. Endo E has 97% accuracy and 100% positive predictive value in diagnosing previous H. pylori gastritis. The accuracy of Endo B and Endo C in diagnosing current H. pylori gastritis was 89 and 82% respectively. Endo D has 87% accuracy in diagnosing previous H. pylori gastritis. Conclusion: This study showed that the modified Endo ABC classification enables to accurately determine the H. pylori-infected gastritis status.
Вплив ілеодуоденопластики на перебіг гнійно-некротичного ураження стопи у хворих на цукровий діабет 2 типу
Authors: Podpryatov S. E. , Podpriatov S. S. , Salata V. V. , Ivaha V. V. , Bielousov I. O. , Korchak V. P. , Satsiuk I. V. 
Published: April 2019

Мета роботи: оцінити вплив виконання ілеодуоденопластики на стан перебіг гнійно-некротичного ураження стопи у хворих на цукровий діабет ІІ типу.
Матеріали і методи. Проведено аналіз результатів виконання операції на кишечнику у 21 хворого на цукровий діабет 2 типу, ускладнений гнійно-некротичним ураженням стопи. Ілеодуоденопластика є варіантом виключення дванадцятипалої кишки з проходження їжі та переміщення здухвинної кишки. Серед пацієнтів було 12 чоловіків та 9 жінок, медіана віку 63 роки, інтерквартильний розмах (ІКР) 13 років, з індексом маси тіла (ІМТ) медіана 32,3 кг/см2, ІКР 8,1 кг/см2. Середня тривалість цукрового діабету склала 10 років, ІКР 9 років. Отримували таблетовані глюкозознижуючі препарати 6 пацієнтів, парентерально вводили інсулін 15.
Результати досліджень та їх обговорення. Нормоглікемія без медикаментозної корекції була досягнута впродовж 3 тижнів після виконання ілеодуоденопластики у 19 пацієнтів, потребували прийому метформіну впродовж 2 місяців 2.
Висока ампутація нижньої кінцівки здійснена у 2 пацієнтів через 3 та 6 місяців після виконання ілеодуоденопластики на тлі критичної ішемії стопи. У інших пацієнтів кровотік в артеріях стопи суттєво покращився. У пацієнтів з діабетичною артроостеопатією та гнійним ураженням стопи високу ампутацію не виконували. В термін до 5 років рецидиву ні гіперглікемії, ні діабетичного ураження стопи не спостерігали.
Виконання ілеодуоденопластики є більш ефективним способом лікування гнійно-некротичного ураження стопи у хворих на цукровий діабет 2 типу в порівнянні з іншими способами.