bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multiplex guide RNA expression system and its efficacy for plant genome engineering
Authors: Oh Youngbin , Lee Bora , Kim Hyeonjin , Kim Sang-Gyu 
Published: March 2020

AbstractBackgroundTheStreptococcus pyogenesCRISPR system is composed of a Cas9 endonuclease (SpCas9) and a single-stranded guide RNA (gRNA) harboring a target-specific sequence. Theoretically,SpCas9 proteins could cleave as many targeted loci as gRNAs bind in a genome.ResultsWe introduce a PCR-free multiple gRNA cloning system for editing plant genomes. This method consists of two steps: (1) cloning the annealed products of two single-stranded oligonucleotide fragments harboring a complimentary target-binding sequence on each strand between tRNA and gRNA scaffold sequences in a pGRNA vector; and (2) assembling tRNA-gRNA units from several pGRNA vectors with a plant binary vector containing aSpCas9 expression cassette using the Golden Gate assembly method. We validated the editing efficiency and patterns of the multiplex gRNA expression system in wild tobacco (Nicotiana attenuata) protoplasts and in transformed plants by performing targeted deep sequencing. Two proximal cleavages bySpCas9-gRNA largely increased the editing efficiency and induced large deletions between two cleavage sites.ConclusionsThis multiplex gRNA expression system enables high-throughput production of a single binary vector and increases the efficiency of plant genome editing.
Indications, feasibility, safety, and efficacy of CyberKnife radiotherapy for the treatment of olfactory groove meningiomas: a single institutional retrospective series
Authors: Liu Jianmin , Rojas Rafael , Lam Fred C. , Mirza Farhan A. , Mahadevan Anand , Kasper Ekkehard M. 
Published: March 2020

Abstract
Purpose
To assess the safety and efficacy of CyberKnife® radiotherapy (CKRT) for the treatment of olfactory groove meningiomas (OGMs).

Methods
A retrospective review was performed of 13 patients with OGM treated with CKRT from September 2005 to May 2018 at our institution. Nine patients were treated primarily with CKRT, 3 for residual disease following resection, and 1 for disease recurrence.

Results
Five patients were treated with stereotactic radiosurgery (SRS), 6 with hypofractionated stereotactic radiotherapy (HSRT), and 2 with fractionated stereotactic radiotherapy (FSRT). The median tumor volume was 8.12 cm3. The median prescribed dose was 14.8 Gy for SRS, 27.3 Gy for HSRT, and 50.2 Gy for FSRT. The median maximal dose delivered was 32.27 Gy. Median post treatment follow-up was 48 months. Twelve of 13 patients yielded a 100% regional control rate with a median tumor volume reduction of 31.7%. Six of the 12 patients had reduced tumor volumes while the other 6 had no changes. The thirteenth patient had significant radiation-induced edema requiring surgical decompression. Twelve patients were alive and neurologically stable at the time of the review. One patient died from pneumonia unrelated to his CKRT treatment.

Conclusions
CKRT appears to be safe and effective for the treatment of OGMs.
A roadmap to using historical controls in clinical trials – by Drug Information Association Adaptive Design Scientific Working Group (DIA-ADSWG)
Authors: Ghadessi Mercedeh , Tang Rui , Zhou Joey , Liu Rong , Wang Chenkun , Toyoizumi Kiichiro , Mei Chaoqun , Zhang Lixia , Deng C. Q. , Beckman Robert A. 
Published: March 2020

AbstractHistorical controls (HCs) can be used for model parameter estimation at the study design phase, adaptation within a study, or supplementation or replacement of a control arm. Currently on the latter, there is no practical roadmap from design to analysis of a clinical trial to address selection and inclusion of HCs, while maintaining scientific validity. This paper provides a comprehensive roadmap for planning, conducting, analyzing and reporting of studies using HCs, mainly when a randomized clinical trial is not possible. We review recent applications of HC in clinical trials, in which either predominantly a large treatment effect overcame concerns about bias, or the trial targeted a life-threatening disease with no treatment options. In contrast, we address how the evidentiary standard of a trial can be strengthened with optimized study designs and analysis strategies, emphasizing rare and pediatric indications. We highlight the importance of simulation and sensitivity analyses for estimating the range of uncertainties in the estimation of treatment effect when traditional randomization is not possible. Overall, the paper provides a roadmap for using HCs.
Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis
Authors: Zhou Jun , Zhou Jing , Shen Dan-Ting , Goyal Hemant , Wu Zhi-Qi , Xu Hua-Guo 
Published: March 2020

Abstract
Background
Hemophagocytic Lymphohistiocytosis (HLH) is a rare clinical syndrome with high mortality rate. The diagnosis of HLH draws on a constellation of clinical and laboratory abnormalities including extremely high serum ferritin levels. However, no biomarker has been firmly established as a clinically useful prognostic tool in HLH patients. We aimed to perform a retrospective analysis of two independent cohorts to explore the prognostic value of discharge serum ferritin for newly diagnosed adult HLH patients who recently started treatment. The prognostic value of serum ferritin levels at discharge (will be called as post-treatment ferritin level) was initially evaluated in a “test cohort” of 161 previously untreated consecutive adult HLH patients. It was then validated in a second cohort of 68 consecutive previously untreated patients (validation cohort).

Results
Multivariate analysis revealed that significantly high post-treatment serum ferritin levels (>1050 μg/L) were associated with a higher risk of death and poor overall survival in the test cohort (hazard ratio (HR): 3.176, 95% confidence interval (CI) 1.468–6.869, P = 0.003), and the validation cohort (HR: 13.412, 95%CI 1.716–104.816, P = 0.013). At 6-month follow-up period in the test cohort, patients with a > 81% decrease in the serum ferritin level had a significantly higher probability of survival when compared with the patients with ≥14% increase in the serum ferritin level (94% vs. 31%, P < 0.001). Similar findings were observed on the analysis of the decrease in the serum ferritin level in the validation cohort.

Conclusions
These results suggest that the serum ferritin level can be used as an independent prognostic marker in the adult HLH patients.
Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review
Authors: Wan Hamish W. Y. , Carey Kate A. , D’Silva Arlene , Vucic Steve , Kiernan Matthew C. , Kasparian Nadine A. , Farrar Michelle A. 
Published: March 2020

Abstract
Background
Spinal muscular atrophy (SMA) is a neurodegenerative disease that has a substantial and multifaceted burden on affected adults. While advances in supportive care and therapies are rapidly reshaping the therapeutic environment, these efforts have largely centered on pediatric populations. Understanding the natural history, care pathways, and patient-reported outcomes associated with SMA in adulthood is critical to advancing health policy, practice and research across the disease spectrum. The aim of this study was to systematically review research investigating the healthcare, well-being and lived experiences of adults with SMA.

Methods
In accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analysis guidelines, seven electronic databases were systematically searched until January 2020 for studies examining clinical (physical health, natural history, treatment) and patient-reported (symptoms, physical function, mental health, quality of life, lived experiences) outcomes in adults with SMA. Study risk of bias and the level of evidence were assessed using validated tools.

Results
Ninety-five articles met eligibility criteria with clinical and methodological diversity observed across studies. A heterogeneous clinical spectrum with variability in natural history was evident in adults, yet slow declines in motor function were reported when observational periods extended beyond 2 years. There remains no high quality evidence of an efficacious drug treatment for adults. Limitations in mobility and daily activities associated with deteriorating physical health were commonly reported, alongside emotional difficulties, fatigue and a perceived lack of societal support, however there was no evidence regarding effective interventions.

Conclusions
This systematic review identifies the many uncertainties regarding best clinical practice, treatment response, and long-term outcomes for adults with SMA. This comprehensive identification of the current gaps in knowledge is essential to guide future clinical research, best practice care, and advance health policy with the ultimate aim of reducing the burden associated with adult SMA.
Reversal of ABCB1-related multidrug resistance by ERK5-IN-1
Authors: Wang Fang , Li Delan , Zheng ZongHeng , Kin Wah To Kenneth , Chen Zhen , Zhong Mengjun , Su Xiaodong , Chen Likun , Fu Liwu 
Published: March 2020

Abstract
Background
Inhibition of ABC transporters is considered the most effective way to circumvent multidrug resistance (MDR). In the present study, we evaluated the MDR modulatory potential of ERK5-IN-1, a potent extracelluar signal regulated kinase 5 (ERK5) inhibitor.

Methods
The cytotoxicity and MDR reversal effect of ERK5-IN-1 were assessed by MTT assay. The KBv200-inoculated nude mice xenograft model was used for the in vivo study. Doxorubicin efflux and accumulation were measured by flow cytometry. The modulation of ABCB1 activity was measured by colorimetric ATPase assay and [125I]-iodoarylazidoprazosin (IAAP) photolabeling assay. Effect of ERK5-IN-1 on expression of ABCB1 and its downstream markers was measured by PCR and/or Western blot. Cell surface expression and subcellular localization of ABCB1 were tested by flow cytometry and immunofluorescence.

Results
Our results showed that ERK5-IN-1 significantly increased the sensitivity of vincristine, paclitaxel and doxorubicin in KBv200, MCF7/adr and HEK293/ABCB1 cells, respectively. This effect was not found in respective drug sensitive parental cell lines. Moreover, in vivo combination studies showed that ERK5-IN-1 effectively enhanced the antitumor activity of paclitaxel in KBv200 xenografts without causing addition toxicity. Mechanistically, ERK5-IN-1 increased intracellular accumulation of doxorubicin dose dependently by directly inhibiting the efflux function of ABCB1. ERK5-IN-1 stimulated the ABCB1 ATPase activity and inhibited the incorporation of [125I]-iodoarylazidoprazosin (IAAP) into ABCB1 in a concentration-dependent manner. In addition, ERK5-IN-1 treatment neither altered the expression level of ABCB1 nor blocked the phosphorylation of downstream Akt or Erk1/2. No significant reversal effect was observed on ABCG2-, ABCC1-, MRP7- and LRP-mediated drug resistance.

Conclusions
Collectively, these results indicated that ERK5-IN-1 efficiently reversed ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function. The use of ERK5-IN-1 to restore sensitivity to chemotherapy or to prevent resistance could be a potential treatment strategy for cancer patients.
Assisted mechanical ventilation promotes recovery of diaphragmatic thickness in critically ill patients: a prospective observational study
Authors: Grassi Alice , Ferlicca Daniela , Lupieri Ermes , Calcinati Serena , Francesconi Silvia , Sala Vittoria , Ormas Valentina , Chiodaroli Elena , Abbruzzese Chiara , Curto Francesco , Sanna Andrea , Zambon Massimo , Fumagalli Roberto , Foti Giuseppe , Bellani Giacomo 
Published: March 2020

Abstract
Background
Diaphragm atrophy and dysfunction are consequences of mechanical ventilation and are determinants of clinical outcomes. We hypothesize that partial preservation of diaphragm function, such as during assisted modes of ventilation, will restore diaphragm thickness. We also aim to correlate the changes in diaphragm thickness and function to outcomes and clinical factors.

Methods
This is a prospective, multicentre, observational study. Patients mechanically ventilated for more than 48 h in controlled mode and eventually switched to assisted ventilation were enrolled. Diaphragm ultrasound and clinical data collection were performed every 48 h until discharge or death. A threshold of 10% was used to define thinning during controlled and recovery of thickness during assisted ventilation. Patients were also classified based on the level of diaphragm activity during assisted ventilation. We evaluated the association between changes in diaphragm thickness and activity and clinical outcomes and data, such as ventilation parameters.

Results
Sixty-two patients ventilated in controlled mode and then switched to the assisted mode of ventilation were enrolled. Diaphragm thickness significantly decreased during controlled ventilation (1.84 ± 0.44 to 1.49 ± 0.37 mm, p < 0.001) and was partially restored during assisted ventilation (1.49 ± 0.37 to 1.75 ± 0.43 mm, p < 0.001). A diaphragm thinning of more than 10% was associated with longer duration of controlled ventilation (10 [5, 15] versus 5 [4, 8.5] days, p = 0.004) and higher PEEP levels (12.6 ± 4 versus 10.4 ± 4 cmH2O, p = 0.034). An increase in diaphragm thickness of more than 10% during assisted ventilation was not associated with any clinical outcome but with lower respiratory rate (16.7 ± 3.2 versus 19.2 ± 4 bpm, p = 0.019) and Rapid Shallow Breathing Index (37 ± 11 versus 44 ± 13, p = 0.029) and with higher Pressure Muscle Index (2 [0.5, 3] versus 0.4 [0, 1.9], p = 0.024). Change in diaphragm thickness was not related to diaphragm function expressed as diaphragm thickening fraction.

Conclusion
Mode of ventilation affects diaphragm thickness, and preservation of diaphragmatic contraction, as during assisted modes, can partially reverse the muscle atrophy process. Avoiding a strenuous inspiratory work, as measured by Rapid Shallow Breathing Index and Pressure Muscle Index, may help diaphragm thickness restoration.
Improved recording of work relatedness during patient consultations in occupational primary health care: a cluster randomized controlled trial using routine data
Authors: Atkins Salla , Reho Tiia , Talola Nina , Sumanen Markku , Viljamaa Mervi , Uitti Jukka 
Published: March 2020

Abstract
Background
Prolonging working careers is a key policy goal in ageing populations in Europe, but reaching this goal is complex. Occupational health services are in the best position to contribute towards prolonging working careers through preventing illnesses that cause work disability and early retirement. However, impacting on the trajectory between illness and work disability requires continuity of care and follow up, enabled through identifying patients at risk. We aimed to determine whether a combined educational and electronic reminder system in occupational health care could improve the recording and follow up of primary care visits made by patients at risk of work disability, and whether the system could impact on sickness absence rates.

Methods
This study is a pragmatic, cluster-randomized controlled trial using medical record data. Twenty-two Pihlajalinna Työterveys units were randomized into an intervention group receiving education and electronic reminders or a group receiving usual care through minimization methods. Patient consultation data were extracted from routine Pihlajalinna Työterveys patient registers from 2015 to 2017. In addition, process indicators were collected from the electronic system. Data were cleaned and analysed on an intention-to-treat basis using analysis of covariance.

Results
There was no significant difference between intervention and control units in terms of sickness absences of different duration. Process indicators suggested that there was a change in physicians’ practice of recording patients’ risk of work disability and work-relatedness of visits following the educational intervention.

Conclusion
Education with an electronic reminder can change physicians’ practice, but long-term follow up is needed to determine whether this impacts on patients’ sickness absences.

Trial registration
ISRCTN Registry: ISRCTN45728263. Registered on 12 April 2016.
Why do patients take part in research? An overview of systematic reviews of psychosocial barriers and facilitators
Authors: Sheridan Rebecca , Martin-Kerry Jacqueline , Hudson Joanna , Parker Adwoa , Bower Peter , Knapp Peter 
Published: March 2020

Abstract
Background
Understanding why people take part in health research is critical to improve research efficiency and generalisability. The aim of this overview of systematic reviews was to identify psychosocial determinants of research participation and map them to psychological theory and empirical recruitment research, to identify effective strategies to increase research participation.

Methods
Qualitative and quantitative systematic reviews were systematically identified. No date or language limits were applied. Two reviewers independently selected reviews. Methodological quality was rated using AMSTAR, and poor-quality reviews (scoring 0–3) were excluded. Barriers and facilitators were coded to psychological theory (Theoretical Domains Framework) and empirical recruitment research (recruitment interventions that had been subjected to randomised controlled trial evaluation).

Results
We included 26 systematic reviews (429 unique primary studies), covering a wide range of patient populations and health settings. We identified five groups of facilitators, of which three were dominant (potential for personal benefit, altruism, trust) and appear to be relevant across research setting and design. We identified nine groups of barriers, which were more dependent on the particular study (context, population, design). Two determinants (participant information, social influences) were found to be both barriers and facilitators. Barriers and facilitators could be coded to the Motivation and Opportunity components of the Theoretical Domains Framework; only one was coded to a Capability component. There was some overlap between psychosocial determinants and empirical recruitment research, but some barriers and facilitators had not been tested at all.

Conclusions
Identifying effective recruitment strategies could increase the efficiency and generalisability of primary research. We identified a number of barriers and facilitators that could be addressed by researchers. There is a need for more research to identify effective recruitment strategies that draw on the psychosocial facilitators and barriers identified in this overview.
Camelina sativa meal hydrolysate as sustainable biomass for the production of carotenoids by Rhodosporidium toruloides
Authors: Bertacchi Stefano , Bettiga Maurizio , Porro Danilo , Branduardi Paola 
Published: March 2020

AbstractBackgroundAs the circular economy advocates a near total waste reduction, the industry has shown an increased interest toward the exploitation of various residual biomasses. The origin and availability of biomass used as feedstock strongly affect the sustainability of biorefineries, where it is converted in energy and chemicals. Here, we explored the valorization ofCamelinameal, the leftover residue fromCamelina sativaoil extraction. In fact, in addition toCamelinameal use as animal feed, there is an increasing interest in further valorizing its macromolecular content or its nutritional value.ResultsCamelinameal hydrolysates were used as nutrient and energy sources for the fermentation of the carotenoid-producing yeastRhodosporidium toruloidesin shake flasks. Total acid hydrolysis revealed that carbohydrates accounted for a maximum of 31 ± 1.0% ofCamelinameal. However, because acid hydrolysis is not optimal for subsequent microbial fermentation, an enzymatic hydrolysis protocol was assessed, yielding a maximum sugar recovery of 53.3%. Separate hydrolysis and fermentation (SHF), simultaneous saccharification and fermentation (SSF), and SSF preceded by presaccharification ofCamelinameal hydrolysate produced 5 ± 0.7, 16 ± 1.9, and 13 ± 2.6 mg/L of carotenoids, respectively. Importantly, the presence of water-insoluble solids, which normally inhibit microbial growth, correlated with a higher titer of carotenoids, suggesting that the latter could act as scavengers.ConclusionsThis study paves the way for the exploitation ofCamelinameal as feedstock in biorefinery processes. The process under development provides an example of how different final products can be obtained from this side stream, such as pure carotenoids and carotenoid-enrichedCamelinameal, can potentially increase the initial value of the source material. The obtained data will help assess the feasibility of usingCamelinameal to generate high value-added products.
Fault localization by analyzing failure propagation with samples in cloud computing environment
Authors: Wang Tiantian , Wang Kechao , Su Xiaohong 
Published: March 2020

AbstractWith the development of information technology such as cloud computing, IoT, etc, software becomes the infrastructure. On the one hand, it is critical to ensure the reliability of software, on the other, sample code can be mined from open source software to provide reference for automatic debugging. Most of existing automated debugging researches are based on the assumption that defect programs are nearly correct, therefore they can successfully pass some test cases and fail to execute others. However, this assumption sometimes does not hold. In view of the fact that a programs may fail for all the given test cases in the test suite, but there are a large number of examples available for reference, a sample based fault localization method is studied. A fault localization method by analyzing the context of failure propagation is proposed, which locates suspicious statements by identifying the execution status and structural semantics differences between the defective program and sample program. Through the interactive analysis of value sequences and structure semantics, the influence of code variations and failure propagation is reduced. The experimental results have shown that the method can effectively locate suspicious statements and provide assistance for defect repair when there are enough sample programs.