bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of exacerbation history on outcomes in the IMPACT trial
Authors: Halpin David M.G. , Dransfield Mark T. , Han MeiLan K. , Jones C. Elaine , Kilbride Sally , Lange Peter , Lipson David A. , Lomas David A. , Martinez Fernando J. , Pascoe Steve , Singh Dave , Wise Robert , Criner Gerard J. 
Published: April 2020

IMPACT, a 52-week, randomised, double-blind trial, assessed the efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapyversusFF/VI or UMEC/VI in patients with symptomatic COPD and a history of exacerbations.Subgroup analyses assessed whether the efficacy of FF/UMEC/VIversusFF/VI or UMEC/VI and UMEC/VIversusFF/VI varies according to prior exacerbation history, and the combined effects of exacerbation history and blood eosinophil counts. Three subgroups were defined: single moderate (1 moderate/no severe; n=3056 (30%)), frequent moderate (≥2 moderate/no severe; n=4628 (45%)) and severe (≥1 severe/any moderate; n=2671 (26%)). End-points included annual on-treatment moderate/severe exacerbation rate (pre-specified), lung function and health status (both post-hoc).Moderate/severe exacerbation rates (reduction % (95% CI)) were reduced in the FF/UMEC/VI groupversusFF/VI (single moderate 20% (10–29), frequent moderate 11% (2–19), severe 17% (7–26)) andversusUMEC/VI (single moderate 18% (5–29), frequent moderate 29% (21–37), severe 26% (14–35)). Moderate/severe exacerbation rates were reduced in the FF/VI groupversusUMEC/VI in the frequent moderate subgroup; a numerical reduction was observed in the severe subgroup (single moderate 2% (−12–18), frequent moderate 21% (11–29), severe 11% (−3–22)). Moderate/severe exacerbation rates were lower in the FF/VI group compared with UMEC/VI in patients with higher eosinophil counts. FF/UMEC/VI improved lung function and health statusversusboth dual therapies irrespective of exacerbation subgroup. UMEC/VI improved lung functionversusFF/VI in all subgroups.Triple therapy was more effective than dual regardless of exacerbation history, consistent with results in the intent-to-treat population. Comparisons between dual therapies were influenced by prior exacerbation history and eosinophil counts.
Performance of immune-based and microbiological tests in children with tuberculosis meningitis in Europe: a multicentre Paediatric Tuberculosis Network European Trials Group (ptbnet) study
Authors: Basu Roy Robindra , Thee Stephanie , Blázquez-Gamero Daniel , Falcón-Neyra Lola , Neth Olaf , Noguera-Julian Antoni , Lillo Cristina , Galli Luisa , Venturini Elisabetta , Buonsenso Danilo , Götzinger Florian , Martinez-Alier Nuria , Velizarova Svetlana , Brinkmann Folke , Welch Steven B. , Tsolia Maria , Santiago-Garcia Begoña , Krüger Renate , Tebruegge Marc 
Published: April 2020

IntroductionTuberculous meningitis (TBM) is often diagnostically challenging. Only limited data exist on the performance of interferon-γ release assays (IGRA) and molecular assays in children with TBM in routine clinical practice, particularly in the European setting.MethodsMulticentre, retrospective study involving 27 healthcare institutions providing care for children with tuberculosis (TB) in nine European countries.ResultsOf 118 children included, 54 (45.8%) had definite, 38 (32.2%) probable and 26 (22.0%) possible TBM; 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2 and 11 (9.3%) grade 3. Of 108 patients who underwent cranial imaging 90 (83.3%) had at least one abnormal finding consistent with TBM. At the 5-mm cut-off the tuberculin skin test had a sensitivity of 61.9% (95% CI 51.2–71.6%) and at the 10-mm cut-off 50.0% (95% CI 40.0–60.0%). The test sensitivities of QuantiFERON-TB and T-SPOT.TB assays were 71.7% (95% CI 58.4–82.1%) and 82.5% (95% CI 58.2–94.6%), respectively (p=0.53). Indeterminate results were common, occurring in 17.0% of QuantiFERON-TB assays performed. Cerebrospinal fluid (CSF) cultures were positive in 50.0% (95% CI 40.1–59.9%) of cases, and CSF PCR in 34.8% (95% CI 22.9–43.7%). In the subgroup of children who underwent tuberculin skin test, IGRA, CSF culture and CSF PCR simultaneously, 84.4% had at least one positive test result (95% CI 67.8%–93.6%).ConclusionsExisting immunological and microbiological TB tests have suboptimal sensitivity in children with TBM, with each test producing false-negative results in a substantial proportion of patients. Combining immune-based tests with CSF culture and CSF PCR results in considerably higher positive diagnostic yields, and should therefore be standard clinical practice in high-resource settings.
Intrapulmonary airway smooth muscle is hyperreactive with a distinct proteome in asthma
Authors: Ijpma Gijs , Kachmar Linda , Panariti Alice , Matusovsky Oleg S. , Torgerson Dara , Benedetti Andrea , Lauzon Anne-Marie 
Published: April 2020

Constriction of airways during asthmatic exacerbation is the result of airway smooth muscle (ASM) contraction. Although it is generally accepted that ASM is hypercontractile in asthma, this has not been unambiguously demonstrated. Whether airway hyperresponsiveness (AHR) is the result of increased ASM mass alone or also increased contractile force generation per unit of muscle directly determines the potential avenues for treatment.To assess whether ASM is hypercontractile we performed a series of mechanics measurements on isolated ASM from intrapulmonary airways and trachealis from human lungs. We analysed the ASM and whole airway proteomes to verify if proteomic shifts contribute to changes in ASM properties.We report an increase in isolated ASM contractile stress and stiffness specific to asthmatic human intrapulmonary bronchi, the site of increased airway resistance in asthma. Other contractile parameters were not altered. Principal component analysis (PCA) of unbiased mass spectrometry data showed clear clustering of asthmatic subjects with respect to ASM specific proteins. The whole airway proteome showed upregulation of structural proteins. We did not find any evidence for a difference in the regulation of myosin activity in the asthmatic ASM.In conclusion, we showed that ASM is indeed hyperreactive at the level of intrapulmonary airways in asthma. We identified several proteins that are upregulated in asthma that could contribute to hyperreactivity. Our data also suggest enhanced force transmission associated with enrichment of structural proteins in the whole airway. These findings may lead to novel directions for treatment development in asthma.
Genetically modified Caenorhabditis elegans may lead to inaccurate toxicity evaluation of mixtures
Authors: Huang Peng , Li Kai , Xu Ya-Qian , Wang Ze-Jun , Liu Shu-Shen 
Published: April 2020

Abstract
Background
One of the major challenges in environmental science is how to assess the toxicity and risk of complex pollutant mixtures. However, only a few studies have pointed out that there is a significant difference between the toxicities of chemicals on genetically modified strains and wild-type organisms and there are few reports of the differences in the toxicity of chemical mixtures. Therefore, six chemicals, two substituted phenols (4-chlorophenol and 4-nitrophenol), two pesticides (dichlorvos and glyphosate) and two ionic liquids (1-butylpyridinium chloride and 1-butylpyridinium bromide), were selected to construct a six-component mixture system, the lethality of various mixtures on the genetically modified Caenorhabditis elegans strain mtl-2::GFP (MTL-2) at 12 and 24 h were determined, and differences in toxicity to other strains were compared.

Results
Although the toxicity of 4-chlorophenol on MTL-2 was not significantly different from that on N2 wild-type Caenorhabditis elegans (N2), the toxicities of the other five chemicals on MTL-2 were greater than those on N2. The toxicities of six single chemicals and nine mixture rays on MTL-2 increased with time, which is consistent with the effect on N2 and on the genetically modified strain sod-3::GFP Caenorhabditis elegans (SOD-3). The toxicological interactions of various mixtures in MTL-2 at 12 h were half antagonistic (ANT) and half additive (ADD), while at 24 h, they were mainly synergistic (SYN). The toxicological interactions of various mixtures in MTL-2 change from ANT/ADD to primarily SYN with time, which is different from the change from ANT to ADD in SOD-3 and from SYN to ADD in N2.

Conclusions
The toxicity and toxicity interactions of chemical mixtures on different Caenorhabditis elegans strains are different. Therefore, it is necessary to examine the effect of genetic factors on the toxicological interaction of mixtures to avoid underestimating or overestimating the mixture risk.
EphB4/ TNFR2/ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation
Authors: Zhang Yu , Yang Chengzhe , Ge Shaohua , Wang Limei , Zhang Jin , Yang Pishan 
Published: April 2020

Abstract
Background
Low concentrations of tumor necrosis factor-alpha (TNF-α) and its receptor TNFR2 are both reported to promote osteogenic differentiation of osteoblast precursor cells. Moreover, low concentrations of TNF-α up-regulate the expression of EphB4. However, the molecular mechanisms underlying TNF-α-induced osteogenic differentiation and the roles of TNFR2 and EphB4 have not been fully elucidated.

Results
The ALP activity, as well as the mRNA and protein levels of RUNX2, BSP, EphB4 and TNFR2, was significantly elevated in MC3T3-E1 murine osteoblast precursor cells when stimulated with 0.5 ng/ml TNF-α. After TNFR2 was inhibited by gene knockdown with lentivirus-mediated shRNA interference or by a neutralizing antibody against TNFR2, the pro-osteogenic effect of TNF-α was partly reversed, while the up-regulation of EphB4 by TNF-α remained unchanged. With EphB4 forward signaling suppressed by a potent inhibitor of EphB4 auto-phosphorylation, NVP-BHG712, TNF-α-enhanced expressions of TNFR2, BSP and Runx2 were significantly decreased. Further investigation into the signaling pathways revealed that TNF-α significantly increased levels of p-JNK, p-ERK and p-p38. However, only the p-ERK level was significantly inhibited in TNFR2-knockdown cells. In addition, the ERK pathway inhibitor, U0126 (10 μM), significantly reversed the positive effect of TNF-α on the protein levels of RUNX2 and BSP.

Conclusions
The EphB4, TNFR2 and ERK/MAPK signaling pathway comprises a signaling axis to mediate the positive effect of TNF-α on osteogenic differentiation.
Forcing external constraints on tree inference using ASTRAL
Authors: Rabiee Maryam , Mirarab Siavash 
Published: April 2020

Abstract
Background
To account for genome-wide discordance among gene trees, several widely-used methods seek to find a species tree with the minimum distance to input gene trees. To efficiently explore the large space of species trees, some of these methods, including ASTRAL, use dynamic programming (DP). The DP paradigm can restrict the search space, and thus, ASTRAL and similar methods use heuristic methods to define a restricted search space. However, arbitrary constraints provided by the user on the output tree cannot be trivially incorporated into such restrictions. The ability to infer trees that honor user-defined constraints is needed for many phylogenetic analyses, but no solution currently exists for constraining the output of ASTRAL.

Results
We introduce methods that enable the ASTRAL dynamic programming to infer constrained trees in an effective and scalable manner. To do so, we adopt a recently developed tree completion algorithm and extend it to allow multifurcating input and output trees. In simulation studies, we show that the approach for honoring constraints is both effective and fast. On real data, we show that constrained searches can help interrogate branches not recovered in the optimal ASTRAL tree to reveal support for alternative hypotheses.

Conclusions
The new algorithm is added ASTRAL to all user-provided constraints on the species tree.
Protocol of a multicentric prospective cohort study for the VALIDation of the IBD-disk instrument for assessing disability in inflammatory bowel diseases: the VALIDate study
Authors: Le Berre C. , Bourreille A. , Flamant M. , Bouguen G. , Siproudhis L. , Dewitte M. , Dib N. , Cesbron-Metivier E. , Goronflot T. , Hanf M. , Gourraud P.-A. , Kerdreux E. , Poinas A. , Trang-Poisson C. 
Published: April 2020

Abstract
Background
Inflammatory Bowel Diseases (IBD) affect psychological, family, social and professional dimensions of patients’ life, leading to disability which is essential to quantify as part of Patient-Reported Outcomes (PROs) newly included in the targets to reach in IBD patients. Up to now, the IBD-Disability Index (IBD-DI) was the only validated tool to assess disability, but it is not appropriate for use in clinical practice. The IBD Disk was developed, a shortened and self-administered tool, adapted from the IBD-DI, in order to give immediate representation of patient-reported disability. However, the IBD Disk has not been validated yet in clinical practice. The aims of the VALIDate study are to validate this tool in a large population of IBD patients and to compare it to the already validated IBD-DI.

Methods
The VALIDate study is an ongoing multicentric prospective cohort study launched in April 2018 in 3 French University Hospitals (Nantes, Rennes, Angers), with an objective to reach a sample of 400 patients over a period inclusion of 6 months. Each patient will fill in the two questionnaires IBD Disk and IBD-DI at baseline, then between 3 and 12 months later, during a follow-up visit. Clinical and socio-demographic data will also be collected. During these two consultations, gastroenterologists and patients will evaluate disease activity thanks to a semi-quantitative 4-grade scale, named respectively PGA (Physician Global Assessment) and PtGA (Patient Global Assessment). This cohort will allow to evaluate the validity of the IBD Disk with respect to the IBD-DI in order to generalize its use for clinical practice. Other psychometric criteria of the IBD Disk will also be analysed as its reliability or its discriminant capacity. Close attention will nonetheless be needed to minimize the number of lost to follow-up patients between baseline and follow-up.

Discussion
The VALIDate study is the study designed to validate the IBD Disk, a visual tool easily useable in daily practice to assess disability in IBD patients. The results of this trial should enable the diffusion of this tool.

Trial registration
The trial is registered in ClinicalTrials.Gov with registration number NCT03590639. First posted: July 18, 2018.
A comparative analysis on human resources among the specialized ophthalmic medical institutions in China
Authors: Zhan Leilei , Safaya Neha , Erkou Hana , An Lei , Wang Zhifeng , Feng Jingjing , Xu Xiao 
Published: April 2020

Abstract
Background
This study compares perspectives on specialized ophthalmic medical institutions, identifies the gaps in property and geographic offerings, and explores the ways that ophthalmic medical institutions can better allocate resources. The results of this research will increase patient’s access to equitable and high-quality ophthalmic care in China.

Methods
The data for this research was gathered from the Survey of China National Eye Care Capacity and Resource for the year 2015. The paper specified the number, professional level of expertise, and educational background of ophthalmic health personnel. The authors of the paper analyzed and compared the differences in ophthalmic care in public vs. private and urban vs. rural regions in China. Descriptive statistics were used.

Results
Of the 395 specialized ophthalmic hospitals surveyed, 332 were private medical institutions (84%), and 63 were public (16%). Of the 26 607 ophthalmic personnel surveyed, working in specialized ophthalmic hospitals, 17 561 were in private hospitals (66%) and 9 046 were in public ones (34%). Furthermore, 22 578 of those personnel worked in urban ophthalmic institutions (85%) and 4 029 worked in rural ones (15%). As for regional differences, 14 090 personnel were located in eastern China (53%), 8 828 in central regions (33%), and 3 689 in the western regions (14%).

Conclusions
Public ophthalmic medical institutions still face challenges in providing equitable and widespread care. The availability of well-staffed health centers varies significantly by region. These variations impact resource allocation and directly lead to inequalities and inaccessibility of health services in certain regions of China.
Intracranial pressure elevation alters CSF clearance pathways
Authors: Vinje Vegard , Eklund Anders , Mardal Kent-Andre , Rognes Marie E. , Støverud Karen-Helene 
Published: April 2020

Abstract
Background
Infusion testing is a common procedure to determine whether shunting will be beneficial in patients with normal pressure hydrocephalus. The method has a well-developed theoretical foundation and corresponding mathematical models that describe the CSF circulation from the choroid plexus to the arachnoid granulations. Here, we investigate to what extent the proposed glymphatic or paravascular pathway (or similar pathways) modifies the results of the traditional mathematical models.

Methods
We used a compartment model to estimate pressure in the subarachnoid space and the paravascular spaces. For the arachnoid granulations, the cribriform plate and the glymphatic circulation, resistances were calculated and used to estimate pressure and flow before and during an infusion test. Finally, different variations to the model were tested to evaluate the sensitivity of selected parameters.

Results
At baseline intracranial pressure (ICP), we found a very small paravascular flow directed into the subarachnoid space, while 60% of the fluid left through the arachnoid granulations and 40% left through the cribriform plate. However, during the infusion, 80% of the fluid left through the arachnoid granulations, 20% through the cribriform plate and flow in the PVS was stagnant. Resistance through the glymphatic system was computed to be 2.73 mmHg/(mL/min), considerably lower than other fluid pathways, giving non-realistic ICP during infusion if combined with a lymphatic drainage route.

Conclusions
The relative distribution of CSF flow to different clearance pathways depends on ICP, with the arachnoid granulations as the main contributor to outflow. As such, ICP increase is an important factor that should be addressed when determining the pathways of injected substances in the subarachnoid space. Our results suggest that the glymphatic resistance is too high to allow for pressure driven flow by arterial pulsations and at the same time too small to allow for a direct drainage route from PVS to cervical lymphatics.
The value of moderate dose escalation for re-irradiation of recurrent or second primary head-and-neck cancer
Authors: Rühle Alexander , Sprave Tanja , Kalckreuth Tobias , Stoian Raluca , Haehl Erik , Zamboglou Constantinos , Laszig Roland , Knopf Andreas , Grosu Anca-Ligia , Nicolay Nils H. 
Published: April 2020

Abstract
Background
Treatment for local and locoregional recurrence or second head-and-neck (H&N) cancers after previous radiotherapy is challenging, and re-irradiation carries a significantly increased risk for radiotherapy-related normal tissue toxicities and treatment failure due to a radioresistant tumor phenotype. Here, we analyzed re-irradiation management and outcomes in patients with recurrent or second primary H&N carcinoma using state-of-the-art diagnostic procedures and radiotherapy techniques.

Methods
Between 2010 and 2019, 48 patients with recurrent or second primary H&N carcinoma received re-radiotherapy at the University of Freiburg Medical Center and were included in this study. Overall survival (OS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method, and univariate Cox-regression analyses were performed to assess the effects of clinico-pathological factors on treatment outcomes. Acute and chronic treatment-related toxicities were quantified using the Common Terminology Criteria for Adverse Events (CTCAE v4.03).

Results
Thirty-one patients (64.6%) received definitive and 17 (35.4%) adjuvant radiotherapy. Simultaneous chemotherapy was administered in 28 patients (58.3%) with cetuximab as the most commonly used systemic agent (n = 17, 60.7%). After a median time of 17 months (range 4 months to 176 months) between first and second radiotherapy, patients were re-irradiated with a median of 58.4 Gy and a treatment completion rate of 87.5% (n = 42). Median OS was 25 months with a 1-year OS amounting to 62.4%, and median PFS was 9 months with a 1-year PFS of 37.6%. Univariate analyses demonstrated that both a lower rT-status and a radiotherapy boost were associated with improved OS (p < 0.05). There was a trend towards superior OS for patients who received > 50 Gy (p = 0.091) and who completed the prescribed radiotherapy (p = 0.055). Five patients (10.4%) suffered from at least one grade 3 toxicities, while 9 patients (27.3%) experienced chronic higher-grade toxicities (≥ grade 3) with one (3.0%) grade 4 carotid blowout and one (3.0%) grade 4 osteoradionecrosis.

Conclusion
Re-irradiation of recurrent or second primary H&N cancer with modern radiation techniques such as intensity-modulated radiotherapy resulted in promising survival rates with acceptable toxicities compared to historical cohorts. Increased re-irradiation doses, utilization of a radiotherapy boost and completion of the re-irradiation treatment were found to result in improved survival.