bluuebunny/crossref_metadata_2025_split huggingface dataset:
Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network
Authors:   the MetabERN collaboration group, Heard Jean-Michel , Vrinten Charlotte , Schlander Michael , Bellettato Cinzia Maria , van Lingen Corine , Scarpa Maurizio 
Published: January 2020

Abstract
Background
The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre.

Results
Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients’ clinical status, characteristic, and personal choice.

Conclusions
Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.
Opportunities and challenges for delivering non-communicable disease management and services in fragile and post-conflict settings: perceptions of policy-makers and health providers in Sierra Leone
Authors: Witter Sophie , Zou Guanyang , Diaconu Karin , Senesi Reynold G. B. , Idriss Ayesha , Walley John , Wurie Haja Ramatulai 
Published: January 2020

Abstract
Background
The growing burden of non-communicable diseases in low- and middle-income countries presents substantive challenges for health systems. This is also the case in fragile, post-conflict and post-Ebola Sierra Leone, where NCDs represent an increasingly significant disease burden (around 30% of adult men and women have raised blood pressure). To date, documentation of health system challenges and opportunities for NCD prevention and control is limited in such settings. This paper aims to identify opportunities and challenges in provision of NCD prevention and care and highlight lessons for Sierra Leone and other fragile states in the battle against the growing NCD epidemic.

Methods
This paper focuses on the case of Sierra Leone and uses a combination of participatory group model building at national and district level, in rural and urban districts, interviews with 28 key informants and review of secondary data and documents. Data is analysed using the WHO’s health system assessment guide for NCDs.

Results
We highlight multiple challenges typical to those encountered in other fragile settings to the delivery of preventive and curative NCD services. There is limited government and donor commitment to financing and implementation of the national NCD policy and strategy, limited and poorly distributed health workforce and pharmaceuticals, high financial barriers for users, and lack of access to quality-assured medicines with consequent high recourse to private and informal care seeking. We identify how to strengthen the system within existing (low) resources, including through improved clinical guides and tools, more effective engagement with communities, and regulatory and fiscal measures.

Conclusion
Our study suggests that NCD prevention and control is of low but increasing priority in Sierra Leone; challenges to addressing this burden relate to huge numbers with NCDs (especially hypertension) requiring care, overall resource constraints and wider systemic issues, including poorly supported primary care services and access barriers. In addition to securing and strengthening political will and commitment and directing more resources and attention towards this area, there is a need for in-depth exploratory and implementation research to shape and test NCD interventions in fragile and post-conflict settings.
Lipid droplets in granulosa cells are correlated with reduced pregnancy rates
Authors: Raviv Shira , Hantisteanu Shay , Sharon Shilhav Meisel , Atzmon Yuval , Michaeli Mediea , Shalom-Paz Einat 
Published: January 2020

Abstract
Background
Lipids are an important source for energy production during oocyte maturation. The accumulation of intracellular lipids binds to proteins to form lipid droplets. This may lead to cellular lipotoxicity. The impact of lipotoxicity on cumulus and granulosa cells has been reported. This pilot study evaluated their correlation to oocyte and embryo quality.

Design
Prospective case-control study.
Setting: Referral IVF unit.
Patients: Women younger than age 40, undergoing IVF with intracytoplasmic sperm injection.
Interventions: 15 women with BMI > 30 (high BMI) and 26 women with BMI < 25 (low BMI) were enrolled. IVF outcomes were compared between groups based on BMI. Lipid content in cumulus and granulosa cells was evaluated using quantitative and descriptive methods. Lipid profile, hormonal profile and C-reactive protein were evaluated in blood and follicular fluid samples. Demographic and treatment data, as well as pregnancy rates were collected from electronic medical records.

Results
Higher levels of LDL and CRP, slower cell division rate and lower embryo quality were found in the group with high BMI. There was no difference in pregnancy rates between groups. In light of these findings, treatment outcomes were reanalyzed according to patients who became pregnant and those who did not. We found that patients who conceived had significantly lower fat content in the granulosa cells, reflected by mean fluorescence intensity recorded by flow cytometry analysis (23,404 vs. 9370, P = 0.03).

Conclusions
BMI has no effect on lipid content in cumulus and granulosa cells, and does not affect likelihood of pregnancy. However, women who achieved pregnancy, regardless of their BMI, had lower lipid levels in their granulosa cells. This finding is important and further study is needed to evaluate lipid content in granulosa cells as a potential predictor of IVF treatment success.
Pharmacological conditioning in the treatment of recent-onset rheumatoid arthritis: a randomized controlled trial study protocol
Authors: Manaï Meriem , van Middendorp Henriët , Veldhuijzen Dieuwke S. , van der Pol Joy A. , Huizinga Tom W. J. , Evers Andrea W. M. 
Published: January 2020

AbstractBackgroundIn pharmacological conditioning associations are formed between the effects of medication and contextual factors related to the medication. Pharmacological conditioning with placebo medication can result in comparable treatment effects and reduced side effects compared to regular treatment in various clinical populations, and may be applied to achieve enhanced drug effects. In the current study protocol, pharmacological conditioning is applied to achieve enhanced treatment effects in patients with recent-onset rheumatoid arthritis (RA). The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness for patients with inflammatory conditions, such as recent-onset RA.MethodsA multicenter, randomized controlled clinical trial is conducted in patients with recent-onset RA. Participants start on standardized pharmacological treatment for 16 weeks, which consists of methotrexate (MTX) 15 mg/week and a tapered schedule of prednisone 60 mg or 30 mg. After 4 months, participants in clinical remission (based on the rheumatologist’s opinion and a targeted score below 1.6 on a 44-joint disease activity score (DAS44)) are randomized to 1 of 2 groups: (1) the control group (C), which continues with a standardized treatment schedule of MTX 15 mg/week or (2) the pharmacological conditioning group (PC), which receives an MTX treatment schedule in alternating high and low dosages. In the case of persistent clinical remission after 8 months, treatment is tapered and discontinued linearly in the C group and variably in the PC group. Both groups receive the same cumulative amount of MTX during each period. Logistic regression analysis is used to compare the proportion of participants with drug-free clinical remission after 12 months between the C group and the PC group. Secondary outcome measures include clinical functioning, laboratory assessments, and self-reported measures after each 4-month period up to 18 months after study start.DiscussionThe results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness in patients with inflammatory conditions, such as recent-onset RA.Trial registrationNetherlands Trial Register,NL5652. Registered on 3 March 2016.
The effectiveness of negative-pressure wound therapy for wound healing after stoma reversal: a randomised control study (SR-PICO study)
Authors: Kim Sohyun , Kang Sung Il 
Published: January 2020

Abstract
Background
Although the wound-healing period for purse-string closure (PSC) after stoma reversal is longer than that required for the primary closure method, the rate of wound infection is reduced. The application of negative-pressure wound therapy (NPWT) can reduce the healing period for many types of wounds. Herein, we describe a planned trial to test the hypothesis that NPWT can reduce the healing period for PSC after stoma reversal.

Methods/design
Patients undergoing stoma reversal will be recruited and allocated into intervention and control groups, with 1:1 randomisation. Patients in the control group will receive standard postsurgical wound care; patients in the intervention group will receive NPWT using the PICO™ system. The target sample size will be 38 patients, as this will provide 80% power at the 5% level of significance to detect a 7-day reduction in the wound-healing period in the intervention group compared to that in the control group. The primary endpoint will be the duration to wound healing, defined as the time to nearly complete epithelisation of the wound, without any discharge or surgical site infection (SSI). Secondary endpoints will be the SSI rate, length of postoperative hospital stay, number of wound dressings and visits to the hospital for wound dressing after discharge, total cost of wound dressings, and patient and observer scar assessment scale scores.

Discussion
The results of this planned randomised controlled study will clarify the role of NPWT in patients undergoing stoma reversal and strengthen the rationale for choosing a dressing technique.

Trial registration
Clinical Research Information Service (CRIS), KCT0004063. Registered on 6 June 2019.
Total utilization of lignin and carbohydrates in Eucalyptus grandis: an integrated biorefinery strategy towards phenolics, levulinic acid, and furfural
Authors: Chen Xue , Zhang Kaili , Xiao Ling-Ping , Sun Run-Cang , Song Guoyong 
Published: January 2020

Abstract
Background
Lignocellulosic biomass, which is composed of cellulose, hemicellulose and lignin, represents the most abundant renewable carbon source with significant potential for the production of sustainable chemicals and fuels. Current biorefineries focus on cellulose and hemicellulose valorization, whereas lignin is treated as a waste product and is burned to supply energy to the biorefineries. The depolymerization of lignin into well-defined mono-aromatic chemicals suitable for downstream processing is recognized increasingly as an important starting point for lignin valorization. In this study, conversion of all three components of Eucalyptus grandis into the corresponding monomeric chemicals was investigated using solid and acidic catalyst in sequence.

Results
Lignin was depolymerized into well-defined monomeric phenols in the first step using a Pd/C catalyst. The maximum phenolic monomers yield of 49.8 wt% was achieved at 240 °C for 4 h under 30 atm H2. In the monomers, 4-propanol guaiacol (12.9 wt%) and 4-propanol syringol (31.9 wt%) were identified as the two major phenolic products with 90% selectivity. High retention of cellulose and hemicellulose pulp was also obtained, which was treated with FeCl3 catalyst to attain 5-hydroxymethylfurfural, levulinic acid and furfural simultaneously. The optimal reaction condition for the co-conversion of hemicellulose and cellulose was established as 190 °C and 100 min, from which furfural and levulinic acid were obtained in 55.9% and 73.6% yields, respectively. Ultimately, 54% of Eucalyptus sawdust can be converted into well-defined chemicals under such an integrated biorefinery method.

Conclusions
A two-step process (reductive catalytic fractionation followed by FeCl3 catalysis) allows the fractionation of all the three biopolymers (cellulose, hemicellulose, and lignin) in Eucalyptus biomass, which provides a promising strategy to make high-value chemicals from sustainable biomass.
Rapid direct identification of positive paediatric blood cultures by MALDI-TOF MS technology and its clinical impact in the paediatric hospital setting
Authors: Samaranayake Waniganeththi Arachchige Manori Piy , Dempsey Suzanne , Howard-Jones Annaleise R. , Outhred Alexander Conrad , Kesson Alison Margaret 
Published: January 2020

Abstract
Objective
Rapid diagnostic tools are imperative for timely clinical decision making, particularly in bacteraemic patients. This study evaluated the performance of a fast, inexpensive novel in house method for processing positive blood cultures for immediate identification of microorganisms by matrix-assisted laser desorption ionization-time of flight mass spectrometry (Vitek MS bioMérieux). We prospectively analyzed the clinical impact of such method on the management of pediatric patients.

Result
In total, 360 positive blood cultures were included. Among 318 mono-microbial cultures, in-house method achieved correct identification in 270 (85%) cultures to the species level, whilst 43 (13.5%) gave no identification, and 7 (2.2%) gave discordant identifications. Identification of Gram-negative organisms was accurate to both species and genus level in 99% of isolates, and for Gram positives accuracy was 84% to genus and 81% to species level overall, with accuracy of 100% for Staphylococcus aureus and Enterococcus to the species level. Assessment of the potential impact of direct identification in sixty sequential cases revealed a clear clinical benefit in 35.5% of cases. Benefits included timely antibiotic rationalization, change of medical intervention, and early confirmation of contamination. This study demonstrates a highly accurate in-house method with considerable potential clinical benefits for paediatric care.
The effect of amyloid deposition on longitudinal resting-state functional connectivity in cognitively normal older adults
Authors: Lin Chemin , Ly Maria , Karim Helmet T. , Wei Wenjing , Snitz Beth E. , Klunk William E. , Aizenstein Howard J. 
Published: January 2020

Abstract
Background
Pathological processes contributing to Alzheimer’s disease begin decades prior to the onset of clinical symptoms. There is significant variation in cognitive changes in the presence of pathology, functional connectivity may be a marker of compensation to amyloid; however, this is not well understood.

Methods
We recruited 64 cognitively normal older adults who underwent neuropsychological testing and biannual magnetic resonance imaging (MRI), amyloid imaging with Pittsburgh compound B (PiB)-PET, and glucose metabolism (FDG)-PET imaging for up to 6 years. Resting-state MRI was used to estimate connectivity of seven canonical neural networks using template-based rotation. Using voxel-wise paired t-tests, we identified neural networks that displayed significant changes in connectivity across time. We investigated associations among amyloid and longitudinal changes in connectivity and cognitive function by domains.

Results
Left middle frontal gyrus connectivity within the memory encoding network increased over time, but the rate of change was lower with greater amyloid. This was no longer significant in an analysis where we limited the sample to only those with two time points. We found limited decline in cognitive domains overall. Greater functional connectivity was associated with better attention/processing speed and executive function (independent of time) in those with lower amyloid but was associated with worse function with greater amyloid.

Conclusions
Increased functional connectivity serves to preserve cognitive function in normal aging and may fail in the presence of pathology consistent with compensatory models.
Cache-enabled physical-layer secure game against smart uAV-assisted attacks in b5G NOMA networks
Authors: Li Chao , Gao Zihe , Xia Junjuan , Deng Dan , Fan Liseng 
Published: January 2020

AbstractThis paper investigates cache-enabled physical-layer secure communication in a no-orthogonal multiple access (NOMA) network with two users, where an intelligent unmanned aerial vehicle (UAV) is equipped with attack module which can perform as multiple attack modes. We present a power allocation strategy to enhance the transmission security. To this end, we propose an algorithm which can adaptively control the power allocation factor for the source station in NOMA network based on reinforcement learning. The interaction between the source station and UAV is regarded as a dynamic game. In the process of the game, the source station adjusts the power allocation factor appropriately according to the current work mode of the attack module on UAV. To maximize the benefit value, the source station keeps exploring the changing radio environment until the Nash equilibrium (NE) is reached. Moreover, the proof of the NE is given to verify the strategy we proposed is optimal. Simulation results prove the effectiveness of the strategy.
Superconvergence of the function value for pentahedral finite elements for an elliptic equation with varying coefficients
Authors: Liu Jinghong , Zhu Qiding 
Published: January 2020

AbstractIn this article, for an elliptic equation with varying coefficients, we first derive an interpolation fundamental estimate for the $\mathcal{P}_{2}(x,y)\otimes \mathcal{P}_{2}(z)$P2(x,y)⊗P2(z) pentahedral finite element over uniform partitions of the domain. Then combined with the estimate for the $W^{2,1}$W2,1-seminorm of the discrete Green function, superconvergence of the function value between the finite element approximation and the corresponding interpolant to the true solution is given.
Dynamics analysis of a delayed virus model with two different transmission methods and treatments
Authors: Zhang Tongqian , Wang Junling , Li Yuqing , Jiang Zhichao , Han Xiaofeng 
Published: January 2020

AbstractIn this paper, a delayed virus model with two different transmission methods and treatments is investigated. This model is a time-delayed version of the model in (Zhang et al. in Comput. Math. Methods Med. 2015:758362, 2015). We show that the virus-free equilibrium is locally asymptotically stable if the basic reproduction number is smaller than one, and by regarding the time delay as a bifurcation parameter, the existence of local Hopf bifurcation is investigated. The results show that time delay can change the stability of the endemic equilibrium. Finally, we give some numerical simulations to illustrate the theoretical findings.
The role of environmental influences in the complex relationship between borderline personality disorder and attention-deficit/hyperactivity disorder: review of recent findings
Authors: Calvo Natalia , Lara Benjamin , Serrat Laia , Pérez-Rodríguez Violeta , Andión Òscar , Ramos-Quiroga Josep A. , Ferrer Marc 
Published: January 2020

Abstract
Background
In recent years, the existence of possible developmental pathways from childhood Attention-Deficit/Hyperactivity Disorder (ADHD) to adult Borderline Personality Disorder (BPD) has been suggested. The existence of common genetic factors has been described but there is little evidence on the role of environmental factors in the possible transition from one disorder to another throughout life. The main goal of this work is to review the literature about the existing evidence on childhood traumas as factors that mediate the risk of developing BPD in children with ADHD.

Methods
A literature search was conducted using PubMed, Science Direct and PsychInfo databases. Criteria included studies of BPD and ADHD relationships and childhood traumas as environmental influences from epidemiological or clinical samples.

Results
The review only identified 4 studies that matched the search criteria. All studies retrospectively analyzed childhood traumas, and adult patients with BPD, with or without comorbid ADHD, were the most frequently mentioned. The analyzed evidence reinforces the relationship between the number of childhood traumas and higher clinical severity. Three of these analyzed studies describe an increased the risk of children with ADHD who report emotional and sexual traumatic experiences to develop BPD in adulthood.

Conclusions
The experience of traumatic childhood events, especially those of an emotional type, may have a mediating effect of an increased risk of developing adult BPD in childhood ADHD patients. However, to consider them as risk factors, more studies, and especially longitudinal studies, are necessary to clarify the probable transactional process between the two disorders. Evidence from these studies may be helpful to develop early intervention programs to reduce the functional impairment associated with the two disorders.