bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ACROSS study: Long-term efficacy of fingolimod in patients with relapsing–remitting multiple sclerosis
Authors: Derfuss T , Sastre-Garriga J , Montalban X , Rodegher M , Wuerfel J , Gaetano L , Tomic D , Azmon A , Wolf C , Kappos L 
Published: March 2020

Background In chronic diseases such as multiple sclerosis requiring lifelong treatment, studies on long-term outcomes are important. Objective To assess disability and magnetic resonance imaging-related outcomes in relapsing multiple sclerosis patients from a Phase 2 study of fingolimod 10 or more years after randomization and to compare outcomes in patients who had a higher fingolimod exposure versus those with a lower fingolimod exposure. Methods ACROSS was a cross-sectional follow-up study of patients originally enrolled in a Phase 2 fingolimod proof-of-concept study (NCT00333138). Disability and magnetic resonance imaging-related outcomes were assessed in patients grouped according to fingolimod treatment duration, based on an arbitrary cut-off: ≥8 years (high exposure) and <8 years (low exposure). Results Overall, 175/281 (62%) patients participated in ACROSS; 104 (59%) of these were classified “high exposure.” At 10 years, patients in the high-exposure group had smaller increases in Expanded Disability Status Scale (+0.55 vs. +1.21), and lower frequencies of disability progression (34.7% vs. 56.1%), wheelchair use (4.8% vs. 16.9%), or transition to secondary progressive multiple sclerosis (9.6% vs. 22.5%) than those in the low-exposure group. The high-exposure patients also had less progression in most magnetic resonance imaging-related outcomes. Conclusion After 10 years of fingolimod treatment, disability progression was lower in the high-exposure group than in the low-exposure group.
Operative Versus Nonoperative Treatment of Acute Achilles Tendon Ruptures: A Pilot Economic Decision Analysis
Authors: Su Alvin W. , Bogunovic Ljiljana , Johnson Jeffrey , Klein Sandra , Matava Matthew J. , McCormick Jeremy , Smith Matthew V. , Wright Rick W. , Brophy Robert H. 
Published: March 2020

Background: The operative treatment of Achilles tendon ruptures has been associated with lower rerupture rates and better function but also a risk of surgery-related complications compared with nonoperative treatment, which may provide improved outcomes with accelerated rehabilitation protocols. However, economic decision analyses integrating the updated costs of both treatment options are limited in the literature. Purpose: To compare the cost-effectiveness of operative and nonoperative treatment of acute Achilles tendon tears. Study Design: Economic and decision analysis; Level of evidence, 2. Methods: An economic decision model was built to assess the cost-utility ratio (CUR) of open primary repair versus nonoperative treatment for acute Achilles tendon ruptures, based on direct costs from the practices of sports medicine and foot and ankle surgeons at a single tertiary academic center, with published outcome probabilities and patient utility data. Multiway sensitivity analyses were performed to reflect the range of data. Results: Nonoperative treatment was more cost-effective in the average scenario (nonoperative CUR, US$520; operative CUR, US$1995), but crossover occurred during the sensitivity analysis (nonoperative CUR range, US$224-US$2079; operative CUR range, US$789-US$8380). Operative treatment cost an extra average marginal CUR of US$1475 compared with nonoperative treatment, assuming uneventful healing in both treatment arms. The sensitivity analysis demonstrated a decreased marginal CUR of operative treatment when the outcome utility was maximized, and rerupture rates were minimized compared with nonoperative treatment. Conclusion: Nonoperative treatment was more cost-effective in average scenarios. Crossover indicated that open primary repair would be favorable for maximized outcome utility, such as that for young athletes or heavy laborers. The treatment decision for acute Achilles tendon ruptures should be individualized. These pilot results provide inferences for further longitudinal analyses incorporating future clinical evidence.
International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI
Authors: Ruppert Amy S. , Dixon Jesse G. , Salles Gilles , Wall Anna , Cunningham David , Poeschel Viola , Haioun Corinne , Tilly Herve , Ghesquieres Herve , Ziepert Marita , Flament Jocelyne , Flowers Christopher , Shi Qian , Schmitz Norbert 
Published: March 2020

Abstract
Great heterogeneity in survival exists for patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL). Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We evaluated 2124 DLBCL patients treated from 1998 to 2009 with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; or variant) across 7 multicenter randomized clinical trials to determine which scoring system best discriminates overall survival (OS). Median age was 63 years, and 56% of patients were male. Five-year OS estimates ranged from 54% to 88%, from 61% to 93%, and from 49% to 92% using the IPI, R-IPI, and NCCN-IPI, respectively. The NCCN-IPI had the greatest absolute difference in OS estimates between the highest- and lowest-risk groups and best discriminated OS (concordance index = 0.632 vs 0.626 [IPI] vs 0.590 [R-IPI]). For each given IPI risk category, NCCN-IPI risk categories were significantly associated with OS (P ≤ .01); the reverse was not true, and the IPI did not provide additional significant prognostic information within all NCCN-IPI risk categories. Collectively, the NCCN-IPI outperformed the IPI and R-IPI. Patients with low-risk NCCN-IPI had favorable survival outcomes with little room for further improvement. In the rituximab era, none of the clinical risk scores identified a patient subgroup with long-term survival clearly &lt;50%. Integrating molecular features of the tumor and microenvironment into the NCCN-IPI or IPI might better characterize a high-risk group for which novel treatment approaches are most needed.
Cerebrovascular disease: how serum phosphorus, vitamin D, and uric acid levels contribute to the ischemic stroke
Authors: Talebi Abolfazl , Amirabadizadeh Alireza , Nakhaee Samaneh , Ahmadi Zahra , Mousavi-Mirzaei Seyed Mohammad 
Published: March 2020

Abstract
Background
Associations between serum phosphorus level and the incidence of ischemic stroke are not clear. This study aimed to measure serum phosphorus, vitamin D3, and uric acid levels in ischemic stroke patients compared to a population without ischemic stroke.

Methods
In this cross-sectional study, 133 patients admitted to a neurology ward with the diagnosis of ischemic stroke were compared with a control group comprising 133 age- and gender-matching individuals. The presence of ischemic stroke was confirmed by a neurologist based on clinical signs, symptoms, brain CT scan, and MRI. Blood samples were taken from all patients in the first 24 h of admission to measure serum phosphorus, vitamin D3, calcium, and uric acid levels.

Results
According to the results of this study, uric acid medians in patients with stroke and controls were 4.9 [3.8–6.4] and 3.9 [3.5–4.9] mg/dL, respectively (p < 0.001). Median phosphorus and vitamin D levels were significantly lower in stroke patients than the controls (3.6 [3.02–4.21] vs. 4.2 [3.8–4.6]) and (15.1 [8.2–27.9] vs. 22.7 [10.4–39.2]), respectively. Multiple logistic regression analysis showed that the ischemic stroke was positively associated with the vitamin D level and negatively correlated with the uric acid level. The phosphorus level was not significantly predictive of ischemic stroke.

Conclusion
Lower serum levels of vitamin D3 and higher levels of uric acid were associated with ischemic stroke. There are still unknowns about the role of these indicators on ischemic stroke and it requires further studies.
Evaluation of the “license, master, doctorate” reform in medical school of University of Lomé (Togo): strengths and weaknesses
Authors: TECLESSOU Julienne Noudé , KPELAO Essossinam , SAKA Bayaki 
Published: March 2020

Abstract
Introduction
The License, Master and Doctorate (LMD) reform that structured high studies in three cycles, has been instituted since the Bologna declaration in 1999. To be conformed to international standards, the LMD system has been instituted in University of Lomé in 2009 to foster pathways between medical and paramedical training. The purpose of this study was to evaluate the strengths and weaknesses of the LMD reform since its introduction in medical school of Lomé.

Method
It was an opinion survey conducted during four months in University of Lomé among the medical school’s teachers about strengths and weaknesses of LMD reform since its application. The strengths were defined as all facilities brought by LMD reform in organization of courses and practices, evaluations, new Information and Communication Technologies (ICTs) (internet, video projector, courses on line). The LMD weaknesses were defined as any problem that it could generate.

Results
Of 113 resident teachers of the medical school of Lomé, seventy-six have completed the questionnaire (67.2%). The majority of teachers (74) thought that the introduction of LMD reform will make Lomé medical school fit into international standards. The availability of the video projectors was mentioned by 90.8% of the teachers and 82.9% of them used it for teaching. Online course was not available. The main strengths of LMD were: a better evaluation system (33.3%), the organization of training in units with credit (28.6%), the usage of new ICTs (23.8%). Respondents also reported many weaknesses of LMD reform: the plethoric number of students (36.2%), the absence of an intermediate diploma and pathways between studies (29.3%). The Insufficiency of human resources and material was also mentioned.

Conclusion
This study highlights that LMD reform needs adaptation to local realities and improvement to ensure that students will get better training in conformity with international standards.
Optimising strategies to address mental ill-health in doctors and medical students: ‘Care Under Pressure’ realist review and implementation guidance
Authors: Carrieri Daniele , Mattick Karen , Pearson Mark , Papoutsi Chrysanthi , Briscoe Simon , Wong Geoff , Jackson Mark 
Published: March 2020

Abstract
Background
Mental ill-health in health professionals, including doctors, is a global and growing concern. The existing literature on interventions that offer support, advice and/or treatment to sick doctors has not yet been synthesised in a way that considers the complexity and heterogeneity of the interventions, and the many dimensions of the problem. We (1) reviewed interventions to tackle doctors’ and medical students’ mental ill-health and its impacts on the clinical workforce and patient care—drawing on diverse literature sources and engaging iteratively with diverse stakeholder perspectives—and (2) produced recommendations that support the tailoring, implementation, monitoring and evaluation of contextually sensitive strategies to tackle mental ill-health and its impacts.

Methods
Realist literature review consistent with the RAMESES quality and reporting standards. Sources for inclusion were identified through bibliographic database searches supplemented by purposive searches—resulting also from engagement with stakeholders. Data were extracted from included articles and subjected to realist analysis to identify (i) mechanisms causing mental ill-health in doctors and medical students and relevant contexts or circumstances when these mechanisms were likely to be ‘triggered’ and (ii) ‘guiding principles’ and features underpinning the interventions and recommendations discussed mostly in policy document, reviews and commentaries.

Results
One hundred seventy-nine records were included. Most were from the USA (45%) and were published since 2009 (74%). The analysis showed that doctors were more likely to experience mental ill-health when they felt isolated or unable to do their job and when they feared repercussions of help-seeking. Healthy staff were necessary for excellent patient care. Interventions emphasising relationships and belonging were more likely to promote wellbeing. Interventions creating a people-focussed working culture, balancing positive/negative performance and acknowledging positive/negative aspects of a medical career helped doctors to thrive. The way that interventions were implemented seemed critically important. Doctors and medical students needed to have confidence in an intervention for the intervention to be effective.

Conclusions
Successful interventions to tackle doctors’ and students’ mental ill-health are likely to be multidimensional and multilevel and involve multiple stakeholders. Evaluating and improving existing interventions is likely to be more effective than developing new ones. Our evidence synthesis provides a basis on which to do this.

Study registration
PROSPERO CRD42017069870. Research project webpage http://sites.exeter.ac.uk/cup/
Retinopathy predicts stroke but not myocardial infarction in type 2 diabetes: the Fremantle Diabetes Study Phase II
Authors: Drinkwater Jocelyn J. , Davis Timothy M. E. , Hellbusch Valentina , Turner Angus W. , Bruce David G. , Davis Wendy A. 
Published: March 2020

Abstract
Background
Microangiopathy in type 2 diabetes (T2D) is associated with cardiovascular disease (CVD), but most relevant studies were performed > 10 years ago. CVD risk factor management has since improved. The aim of this study was to determine whether diabetic retinopathy (DR) and its severity increases stroke and myocardial infarction (MI) risk in a contemporary cohort.

Methods
Fremantle Diabetes Study Phase II participants with T2D had DR graded from fundus photography at baseline between 2008 and 2011. Subsequent hospitalizations and mortality for MI or stroke were ascertained through validated data linkage to end-2016. Cox regression modelling identified predictors of first stroke and MI including DR presence and severity.

Results
The 1521 participants with T2D and known DR status (mean age 65.6 years, 52.1% males, median diabetes duration 9.0 years) were followed for a mean of 6.6 years. After excluding those with prior MI/stroke, there were 126 incident MIs among 1393 eligible participants and 53 incident strokes in 1473 eligible participants, respectively. Moderate non-proliferative DR (NPDR) or worse was significantly and independently associated with an increased risk of incident stroke (adjusted hazard ratio 2.55 (95% CI 1.19, 5.47), p = 0.016). Retinopathy presence and severity increased the risk of incident MI in unadjusted models (p ≤ 0.001), but these associations were no longer statistically significant after adjusting for other risk factors.

Conclusions
Moderate NPDR or worse was associated with an increased risk of first stroke in Australians with T2D. Intensified CVD risk factor management should be considered for patients with at least moderate NPDR.
Cardiac magnetic resonance for asymptomatic patients with type 2 diabetes and cardiovascular high risk (CATCH): a pilot study
Authors: Ng Ming-Yen , Zhou Wenli , Vardhanabhuti Varut , Lee Chi-Ho , Yu Esther Yee Tak , Wan Eric Yuk Fai , Chan Kit , Yan Andrew T. , Ip Tai-Pang , Yiu Kai-Hang , Wintersperger Bernd J. 
Published: March 2020

AbstractBackgroundStress cardiovascular magnetic resonance (CMR) to screen for silent myocardial ischaemia in asymptomatic high risk patients with type 2 diabetes mellitus (DM) has never been performed, and its effectiveness is unknown. Our aim was to determine the feasibility of a screening programme using stress CMR by obtaining preliminary data on the prevalence of silent ischaemia caused by obstructive coronary artery disease (CAD) and quantify myocardial perfusion in asymptomatic high risk patients with type 2 diabetes.MethodsIn this prospective cohort study, we recruited 63 asymptomatic DM patients (mean age 66 years ± 4.4 years; 77.8% male); with Framingham risk score ≥ 20% from 3 sites from June 2017 to August 2018. Normal volunteers were recruited to determine normal global myocardial perfusion reserve index (MPRI). Adenosine stress CMR and global MPRI was performed and measured in all subjects. Positive stress CMR cases were referred for catheter coronary angiography (CCA) with/without fractional flow reserve (FFR) measurements. Positive CCA was defined as an FFR ≤ 0.8 or coronary narrowing ≥ 70%. Patients were followed up for major adverse cardiovascular events. Prevalence is presented as patient numbers and percentage. Mann–Whitney U test was used to compare global MPRI between patients and normal volunteers.Results13 patients had positive stress CMR with positive CCA (20.6% of patient population), while 9 patients with positive stress CMR examinations had a negative CCA. 5 patients (7.9%) had infarcts detected of which 2 patients had no stress perfusion defects. 12 patients had coronary artery stents inserted, whilst 1 patient declined stent placement. DM patients had lower global MPRI than normal volunteers (n = 7) (1.43 ± 0.27 vs 1.83 ± 0.31 respectively; p < 0.01). After a median follow-up of 653 days, there was no death, heart failure, acute coronary syndrome hospitalisation or stroke.Conclusion20.6% of asymptomatic DM patients (with Framingham risk ≥ 20%) had silent obstructive CAD. Furthermore, asymptomatic patients have reduced global MPRI than normal volunteers.Trial Registration:ClinicalTrials.gov Registration Number: NCT03263728 on 28th August 2017;https://clinicaltrials.gov/ct2/show/NCT03263728.
Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging
Authors:   the AIBL Research Group, Doecke James D. , Ward Larry , Burnham Samantha C. , Villemagne Victor L. , Li Qiao-Xin , Collins Steven , Fowler Christopher J. , Manuilova Ekaterina , Widmann Monika , Rainey-Smith Stephanie R. , Martins Ralph N. , Masters Colin L. 
Published: March 2020

Abstract
Background
β-amyloid (Aβ) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer’s disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology.

Methods
Using automated Elecsys® assays (Roche Diagnostics) for Aβ (1–42) (Aβ42), Aβ (1–40) (Aβ40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging.

Results
Ratios Aβ42/Aβ40, tTau/Aβ42 and pTau/Aβ42 had higher receiver operator characteristic—area under the curve (all 0.94), and greater concordance with Aβ-PET (overall percentage agreement ~ 90%), compared with individual biomarkers.

Conclusion
Strong concordance between CSF biomarkers and Aβ-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials.
Epithelial differentiation of human adipose-derived stem cells (hASCs) undergoing three-dimensional (3D) cultivation with collagen sponge scaffold (CSS) via an indirect co-culture strategy
Authors: Li Minxiong , Ma Jun , Gao Yanbin , Dong Mengru , Zheng Zijun , Li Yuchen , Tan Rongwei , She Zhending , Yang Lei 
Published: March 2020

AbstractBackgroundThree-dimensional (3D) cultivation with biomaterials was proposed to facilitate stem cell epithelial differentiation for wound healing. However, whether human adipose-derived stem cells (hASCs) on collagen sponge scaffold (CSS) better differentiate to keratinocytes remains unclear.Methods3D cultivation with CSS on hASC epidermal differentiation co-cultured with HaCaT cells at air-liquid interface (ALI) was compared with two-dimensional (2D) form and cultivation without “co-culture” or “ALI.” Cellular morphology, cell adhesion, and growth condition were evaluated, followed by the protein and gene expression of keratin 14 (K14, keratinocyte specific marker).ResultsTypical cobblestone morphology of keratinocytes was remarkably observed in co-cultured hASCs at ALI, but those seeded on the CSS exhibited more keratinocyte-like cells under an invert microscope and scanning electron microscope. Desired cell adhesion and proliferation were confirmed in 3D differentiation groups by rhodamine-labeled phalloidin staining, consistent with H&E staining. Compared with those cultured in 2D culture system or without “ALI,” immunofluorescence staining and gene expression analysis revealed hASCs co-cultured over CSS expressed K14 at higher levels at day 15.ConclusionsCSS is positive to promote epithelial differentiation of hASCs, which will foster a deeper understanding of artificial dermis in skin wound healing and regeneration.
Comparative transcriptome analysis reveals gene expression differences between two peach cultivars under saline-alkaline stress
Authors: Sun Shuxia , Song Haiyan , Li Jing , Chen Dong , Tu Meiyan , Jiang Guoliang , Yu Guoqing , Zhou Zhiqin 
Published: March 2020

Abstract
Background
Saline-alkaline stress is a major abiotic stress that is harmful to plant growth worldwide. Two peach cultivars (GF677 and Maotao) display distinct phenotypes under saline-alkaline stress. The molecular mechanism explaining the differences between the two cultivars is still unclear.

Results
In the present study, we systematically analysed the changes in GF677 and Maotao leaves upon saline-alkaline stress by using cytological and biochemical technologies as well as comparative transcriptome analysis. Transmission electron microscopy (TEM) observations showed that the structure of granum was dispersive in Maotao chloroplasts. The biochemical analysis revealed that POD activity and the contents of chlorophyll a and chlorophyll b, as well as iron, were notably decreased in Maotao. Comparative transcriptome analysis detected 881 genes with differential expression (including 294 upregulated and 587 downregulated) under the criteria of |log2 Ratio| ≥ 1 and FDR ≤0.01. Gene ontology (GO) analysis showed that all differentially expressed genes (DEGs) were grouped into 30 groups. MapMan annotation of DEGs showed that photosynthesis, antioxidation, ion metabolism, and WRKY TF were activated in GF677, while cell wall degradation, secondary metabolism, starch degradation, MYB TF, and bHLH TF were activated in Maotao. Several iron and stress-related TFs (ppa024966m, ppa010295m, ppa0271826m, ppa002645m, ppa010846m, ppa009439m, ppa008846m, and ppa007708m) were further discussed from a functional perspective based on the phylogenetic tree integration of other species homologues.

Conclusions
According to the cytological and molecular differences between the two cultivars, we suggest that the integrity of chloroplast structure and the activation of photosynthesis as well as stress-related genes are crucial for saline-alkaline resistance in GF677. The results presented in this report provide a theoretical basis for cloning saline-alkaline tolerance genes and molecular breeding to improve saline-alkaline tolerance in peach.