bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial
Authors: Siddharthan Trishul , Pollard Suzanne L. , Jackson Peter , Robertson Nicole M. , Wosu Adaeze C. , Rahman Nihaal , Padalkar Roma , Sekitoleko Isaac , Namazzi Esther , Alupo Patricia , Hurst John R. , Kalyesubula Robert , Dowdy David , Wise Robert , Barnes Peter J. , Checkley William , Kirenga Bruce 
Published: March 2021

Abstract
Background
COPD is a leading cause of death globally, with the majority of morbidity and mortality occurring in low- and middle-income country (LMIC) settings. While tobacco-smoke exposure is the most important risk factor for COPD in high-income settings, household air pollution from biomass smoke combustion is a leading risk factor for COPD in LMICs. Despite the high burden of biomass smoke-related COPD, few studies have evaluated the efficacy of pharmacotherapy in this context. Currently recommended inhaler-based therapy for COPD is neither available nor affordable in most resource-limited settings. Low-dose theophylline is an oral, once-a-day therapy, long used in high-income countries (HICs), which has been proposed for the management of COPD in LMICs in the absence of inhaled steroids and/or bronchodilators. The Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD) trial investigates the clinical efficacy and cost-effectiveness of low-dose theophylline for the management of biomass-related COPD in a low-income setting.

Methods
LODOT-BCOPD is a randomized, double-blind, placebo-controlled trial to test the efficacy of low-dose theophylline in improving respiratory symptoms in 110 participants with moderate to severe COPD in Central Uganda. The inclusion criteria are as follows: (1) age 40 to 80 years, (2) full-time resident of the study area, (3) daily biomass exposure, (4) post-bronchodilator FEV1/FVC below the 5th percentile of the Global Lung Initiative mixed ethnic reference population, and (5) GOLD Grade B-D COPD. Participants will be randomly assigned to receive once daily low-dose theophylline (200 mg ER, Unicontin-E) or placebo for 52 weeks. All participants will receive education about self-management of COPD and rescue salbutamol inhalers. We will measure health status using the St. George’s Respiratory Questionnaire (SGRQ) and quality of life using the EuroQol-5D (EQ-5D) at baseline and every 6 months. In addition, we will assess household air pollution levels, serum inflammatory biomarkers (fibrinogen, hs-CRP), and theophylline levels at baseline, 1 month, and 6 months. The primary outcome is change in SGRQ score at 12 months. Lastly, we will assess the cost-effectiveness of the intervention by calculating quality-adjusted life years (QALYs) from the EQ-5D.

Trial registration
ClinicalTrials.gov NCT03984188. Registered on June 12, 2019

Trial acronym
Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD)
Reproductive injury in male BALB/c mice infected with Neospora caninum
Authors: Li Hang , Yang Bing-Yi , Liu Ming-Ming , Zhao Shao-Wei , Xie Su-Zhu , Wang Hao , Zhang Shuang , Xuan Xue-Nan , Jia Li-Jun 
Published: March 2021

Abstract
Background
Neospora caninum is one of the main causes of abortion in pregnant animals. However, N. caninum-induced reproductive injury in male mice is still unclear.

Methods
Male BALB/c mice were infected with a bovine isolate of N. caninum, and the organ coefficients of the testis and epididymis were measured. Lesions in the testis and epididymis were observed by light microscopy and transmission electron microscopy. Expression of the spermatogenic cell apoptosis-related proteins p53 and caspase-3 was detected by western blot. The expression of spermatogenesis-related genes in the testis was detected by reverse transcription-PCR. Sperm morphology and motility were observed. The levels of nitric oxide (NO) and antisperm antibody (AsAb) in the testicular homogenates and hormones in the serum were detected by enzyme-linked immunosorbent assay. The reproductive capacity of the male mice was detected using a reproduction test.

Results
The organ coefficients of the testis and epididymis of the experimental group were significantly downregulated. Light microscopy examination revealed that the spermatogenic cells of the testis were arranged in a disordered manner, and the number was reduced. The number of sperm in the epididymal lumen was significantly reduced, and the cytoplasm exhibited vacuolation and degeneration. Ultrastructural studies revealed that the cells of the testis and epididymis tissues showed varying degrees of disease. The level of p53 and caspase-3 expression in the testis was significantly upregulated. The expression of the testicular spermatogenesis-related genes Herc4, Ipo11 and Mrto4 were strongly downregulated. Observation of sperm by microscopic examination revealed significantly reduced sperm density and sperm motility, and the number of sperm deformities was significantly increased. The level of NO and AsAb was significantly increased. The levels of luteinizing hormone, follicle-stimulating hormone and gonadotropin-releasing hormone were significantly upregulated, whereas the levels of testosterone, thyrotropin-releasing hormone, thyroxine and thyroid-stimulating hormone were significantly downregulated. After challenge, the infected male mice and healthy female mice were caged together: the subsequent fetal death rate was increased, and the conception rate, litter size, number of live births and the birth weight were significantly reduced.

Conclusions
Infection of male BALB/c mice with the bovine isolate of N. caninum induced varying degrees of injury to the testis, epididymis and sperm of the mice, destroyed spermatogenesis and affected the reproductive capacity.

Graphical Abstract
EGFL6 promotes colorectal cancer cell growth and mobility and the anti‐cancer property of anti-EGFL6 antibody
Authors: Sung Ting-Yi , Huang Han-Li , Cheng Chun-Chun , Chang Fu-Ling , Wei Po-Li , Cheng Ya-Wen , Huang Cheng-Chiao , Lee Yu-Ching , HuangFu Wei-Chun , Pan Shiow-Lin 
Published: March 2021

Abstract
Background
The availability of a reliable tumor target for advanced colorectal cancer (CRC) therapeutic approaches is critical since current treatments are limited. Epidermal growth factor-like domain 6 (EGFL6) has been reported to be associated with cancer development. Here, we focused on the role of EGFL6 in CRC progression and its clinical relevance. In addition, an anti-EGFL6 antibody was generated by phage display technology to investigate its potential therapeutic efficacy in CRC.

Results
EGFL6 expression
significantly increased in the colon tissues from CRC patients and mice showing
spontaneous tumorigenesis, but not in normal tissue. Under hypoxic condition, EGFL6
expression was enhanced at both protein and transcript levels. Moreover, EGFL6
could promote cancer cell migration invasion, and proliferation of CRC cells via up-regulation of
the ERK/ AKT pathway. EGFL6 also regulated cell migration, invasion,
proliferation, and self-renewal through EGFR/αvβ3 integrin receptors. Treatment
with the anti-EGFL6 antibody EGFL6-E5-IgG showed tumor-inhibition and
anti-metastasis abilities in the xenograft and syngeneic mouse models,
respectively. Moreover, EGFL6-E5-IgG treatment had no adverse effect on
angiogenesis and wound healing

Conclusions
We demonstrated that EGFL6 plays a role in CRC tumorigenesis and tumor progression, indicating that EGFL6 is a potential therapeutic target worth further investigation.
When the genome bluffs: a tandem duplication event during generation of a novel Agmo knockout mouse model fools routine genotyping
Authors: Sailer Sabrina , Coassin Stefan , Lackner Katharina , Fischer Caroline , McNeill Eileen , Streiter Gertraud , Kremser Christian , Maglione Manuel , Green Catherine M. , Moralli Daniela , Moschen Alexander R. , Keller Markus A. , Golderer Georg , Werner-Felmayer Gabriele , Tegeder Irmgard , Channon Keith M. , Davies Benjamin , Werner Ernst R. , Watschinger Katrin 
Published: March 2021

Abstract
Background
Genome editing in mice using either classical approaches like homologous recombination or CRISPR/Cas9 has been reported to harbor off target effects (insertion/deletion, frame shifts or gene segment duplications) that lead to mutations not only in close proximity to the target site but also outside. Only the genomes of few engineered mouse strains have been sequenced. Since the role of the ether-lipid cleaving enzyme alkylglycerol monooxygenase (AGMO) in physiology and pathophysiology remains enigmatic, we created a knockout mouse model for AGMO using EUCOMM stem cells but unforeseen genotyping issues that did not agree with Mendelian distribution and enzyme activity data prompted an in-depth genomic validation of the mouse model.

Results
We report a gene segment tandem duplication event that occurred during the generation of an Agmo knockout-first allele by homologous recombination. Only low homology was seen between the breakpoints. While a single copy of the recombinant 18 kb cassette was integrated correctly around exon 2 of the Agmo gene, whole genome nanopore sequencing revealed a 94 kb duplication in the Agmo locus that contains Agmo wild-type exons 1–3. The duplication fooled genotyping by routine PCR, but could be resolved using qPCR-based genotyping, targeted locus amplification sequencing and nanopore sequencing. Despite this event, this Agmo knockout mouse model lacks AGMO enzyme activity and can therefore be used to study its physiological role.

Conclusions
A duplication event occurred at the exact locus of the homologous recombination and was not detected by conventional quality control filters such as FISH or long-range PCR over the recombination sites. Nanopore sequencing provides a cost convenient method to detect such underrated off-target effects, suggesting its use for additional quality assessment of gene editing in mice and also other model organisms.
Direct and indirect evidence of efficacy and safety of rapid exercise tests for exertional desaturation in Covid-19: a rapid systematic review
Authors: Kalin Asli , Javid Babak , Knight Matthew , Inada-Kim Matt , Greenhalgh Trisha 
Published: March 2021

AbstractBackgroundEven when resting pulse oximetry is normal in the patient with acute Covid-19, hypoxia can manifest on exertion. We summarise the literature on the performance of different rapid tests for exertional desaturation and draw on this evidence base to provide guidance in the context of acute Covid-19.Main research questionsWhat exercise tests have been used to assess exertional hypoxia at home or in an ambulatory setting in the context of Covid-19 and to what extent have they been validated?What exercise tests have been used to assess exertional hypoxia in other lung conditions, to what extent have they been validated and what is the applicability of these studies to acute Covid-19?MethodAMED, CINAHL, EMBASE MEDLINE, Cochrane and PubMed using LitCovid, Scholar and Google databases were searched to September 2020. Studies where participants had Covid-19 or another lung disease and underwent any form of exercise test which was compared to a reference standard were eligible. Risk of bias was assessed using QUADAS 2. A protocol for the review was published on the Medrxiv database.ResultsOf 47 relevant papers, 15 were empirical studies, of which 11 described an attempt to validate one or more exercise desaturation tests in lung diseases other than Covid-19. In all but one of these, methodological quality was poor or impossible to fully assess. None had been designed as a formal validation study (most used simple tests of correlation). Only one validation study (comparing a 1-min sit-to-stand test [1MSTST] with reference to the 6-min walk test [6MWT] in 107 patients with interstitial lung disease) contained sufficient raw data for us to calculate the sensitivity (88%), specificity (81%) and positive and negative predictive value (79% and 89% respectively) of the 1MSTST. The other 4 empirical studies included two predictive studies on patients with Covid-19, and two on HIV-positive patients with suspected pneumocystis pneumonia. We found no studies on the 40-step walk test (a less demanding test that is widely used in clinical practice to assess Covid-19 patients). Heterogeneity of study design precluded meta-analysis.DiscussionExertional desaturation tests have not yet been validated in patients with (or suspected of having) Covid-19. A stronger evidence base exists for the diagnostic accuracy of the 1MSTST in chronic long-term pulmonary disease; the relative intensity of this test may raise safety concerns in remote consultations or unstable patients. The less strenuous 40-step walk test should be urgently evaluated.
Murrayanine suppresses the proliferation and metastasis of human breast cancer cells via induction of apoptosis and inhibition of RANK/RANKL signaling pathway
Authors: zhang Jingnan , Wang Feng , Qu Gengbao , Wang Baokai 
Published: March 2021

AbstractMurrayanine and its derivatives have been shown to exhibit anticancer activities against different types of human cancer cells. However, the effects of murrayanine on the proliferation and metastasis of breast cancer cells are yet to be studied. The present study was designed to evaluate the effects of murrayanine on the proliferation and metastasis of human breast cancer via regulation of RANK/RANKL pathway. The results showed RANK/RANKL pathway to be highly activated in human breast cancer tissues and cell lines. However, treatment of the CAMA-1 breast cancer cells with murrayanine (0, 9, 18 and 36 μM) caused a significant (P < 0.05) decline in the expression of RANK, RANKL and OPG in CAMA-1 cells. Additionally, murrayanine inhibited the growth of CAMA-1 cells with an IC50 of 18 μM. The antiproliferative of murrayanine were found be due to its ability to inhibit the expression of RANK, RANKL and OPG in CAMA-1 cells. To unveil if murrayanine exerted its effects via inhibition of RANK/RANKL pathway, the expression of RNAK was knocked down in CAMA-1 cells. It was found that murrayanine and RANK silencing both inhibited the growth CAMA-1 cells via induction of apoptosis. Additionally, murrayanine and RANK silencing both inhibited the migration, invasion and epithelial to mesenchymal transition of the CAMA-1 cells. Taken together, murrayanine exhibits significant anticancer activity against the breast cancer cells via induction of apoptosis and inhibition of RANK/RANKL signaling pathway. These findings suggest that murrayanine may prove to be a beneficial lead molecule for the development of breast cancer chemotherapy.
Barley somatic embryogenesis-an attempt to modify variation induced in tissue culture
Authors: Orłowska Renata 
Published: March 2021

Abstract
Background
Somatic embryogenesis is a phenomenon carried out in an environment that generates abiotic stress. Thus, regenerants may differ from the source of explants at the morphological, genetic, and epigenetic levels. The DNA changes may be the outcome of induction media ingredients (i.e., copper and silver ions) and their concentrations and time of in vitro cultures.

Results
This study optimised the level of copper and silver ion concentration in culture media parallel with the induction medium longevity step towards obtaining barley regenerants via somatic embryogenesis with a minimum or maximum level of tissue culture-induced differences between the donor plant and its regenerants. The optimisation process is based on tissue culture-induced variation evaluated via the metAFLP approach for regenerants derived under varying in vitro tissue culture conditions and exploited by the Taguchi method. In the optimisation and verification experiments, various copper and silver ion concentrations and the different number of days differentiated the tested trials concerning the tissue culture-induced variation level, DNA demethylation, and de novo methylation, including symmetric (CG, CHG) and asymmetric (CHH) DNA sequence contexts. Verification of optimised conditions towards obtaining regenerants with minimum and maximum variability compared to donor plants proved useful. The main changes that discriminate optimised conditions belonged to DNA demethylation events with particular stress on CHG context.

Conclusions
The combination of tissue culture-induced variation evaluated for eight experimental trials and implementation of the Taguchi method allowed the optimisation of the in vitro tissue culture conditions towards the minimum and maximum differences between a source of tissue explants (donor plant) and its regenerants from somatic embryos. The tissue culture-induced variation characteristic is mostly affected by demethylation with preferences towards CHG sequence context.
Optimising medication management in children and young people with ADHD using a computerised test (QbTest): a feasibility randomised controlled trial
Authors: Williams Laura , Hall Charlotte L. , Brown Susan , Guo Boliang , James Marilyn , Franceschini Matilde , Clarke Julie , Selby Kim , Vijayan Hena , Kulkarni Neeta , Brown Nikki , Sayal Kapil , Hollis Chris , Groom Madeleine J. 
Published: March 2021

Abstract
Background
Medication for attention deficit hyperactivity disorder (ADHD) should be closely monitored to ensure optimisation. There is growing interest in using computerised assessments of ADHD symptoms to support medication monitoring. The aim of this study was to assess the feasibility and acceptability of a randomised controlled trial (RCT) to evaluate the efficacy of one such computerised assessment, the Quantified Behavior (Qb) Test, as part of medication management for ADHD.

Methods
This feasibility multi-site RCT conducted in child and adolescent mental health and community paediatric settings recruited participants aged 6–15 years diagnosed with ADHD starting stimulant medication. Participants were randomised into one of two arms: experimental (QbTest protocol) where participants completed a QbTest at baseline and two follow-up QbTests on medication (2–4 weeks and 8–10 weeks later) and control where participants received treatment as usual, including at least two follow-up consultations. Measures of parent, teacher, and clinician-rated symptoms and global functioning were completed at each time point. Clinicians recorded treatment decision-making and health economic measures were obtained. Data were analysed using multi-level modelling and participants (children and parents) and clinicians were interviewed about their experiences, resulting data were thematically analysed.

Results
Forty-four children and young people were randomised. Completion of study outcome measures by care-givers and teachers ranged from 52 to 78% at baseline to 47–65% at follow-up. Participants reported the questionnaires to be useful to complete. SNAP-IV inattention scores showed greater reduction in the intervention than the control group (− 5.85, 95% CI − 10.33, − 1.36,). Engagement with the intervention ranged from 100% at baseline, to 78% follow-up 1 and 57% follow-up 2. However, only 37% of QbTests were conducted in the correct time period. Interview data highlighted that the objectivity of the QbTest was appreciated by clinicians and parents. Clinicians commented that the additional time and resources required meant that it is not feasible to use QbTest for all cases.

Conclusion
The trial design and protocol appear to be feasible and acceptable but could be improved by modifying QbTest time periods and the method of data collection. With these changes, the protocol may be appropriate for a full trial. Adding QbTest may improve symptom outcome as measured by SNAP-IV.

Trial registration
ClinicalTrials.gov, NCT03368573, prospectively registered, 11th December 2017, and ISRCTN, ISRCTN69461593, retrospectively registered, 10th April 2018
Preretinal hemorrhage preventing subretinal involvement in multilayer macular hemorrhages: coincidence or plausible relationship?
Authors: Nascimento Priscila A. , Carbajo Cristina N. , Mendonça Luisa S. M. , Okimoto Juliana T. , Barros Bogdan C. M. , Abucham-Neto Julio Z. 
Published: March 2021

Abstract
Background
To report four cases with interesting anatomical presentations of multilayer macular hemorrhages with preretinal hemorrhage possibly preventing subretinal involvement of the macular area.

Cases presentation
Observational study of four patients presenting with macular hemorrhages.

Results
Four patients with multilayer macular hemorrhage due to different causes, presented with a halo-shaped submacular hemorrhage coincident with the preretinal hemorrhage borders. After resolution, in all cases, the macular area underneath the preretinal hemorrhage was found to be spared.

Conclusion
We hypothesized that an extensive preretinal hemorrhage can exert a mechanical force pushing the subretinal hemorrhage towards the periphery, consequently protecting the macular area.
Pathogenicity of two fungal pathogens on larvae of the elm leaf beetle, Xanthogaleruca luteola Muller (Coleoptera: Chrysomelidae)
Authors: Ebrahimifar Jafar , Jamshidnia Arsalan 
Published: March 2021

Abstract
Background
The elm leaf beetle (ELB), Xanthogaleruca luteola Muller (Coleoptera: Chrysomelidae), is one of the most important insect pests that cause damage and physiological stress for the trees. In the present research, pathogenicity of both entomopathogenic fungi (EPF), Beauveria bassiana and Metarhizium anisopliae on the 1st, 2nd, and 3rd instar larval of ELB at the concentrations of 105, 106, 107, and 108 conidia per ml, using immersion and spray methods and were evaluated.

Results
The results showed that LC50 of B. bassiana in immersion and spray methods were 3.88 × 102 and 7.52 × 102 conidia/ml, while LC50 of M. anisopliae in mentioned methods were 7.05 × 102 and 11.85 × 102 conidia/ml, respectively. The highest mortality rate in both EPF was observed in the 1st instar larvae that were significantly different than the control treatment. Moreover, the highest and lowest mortality in both EPF, using immersion and spray methods, were observed at the concentrations of 108 and 105 conidia/ml, respectively. Therefore, susceptibility of 1st and 2nd larval instars was more than 1st instar larvae. Based on the findings of the present study, there was no mortality during the first 24 h, while after 2 days, the mortality was recorded and increased over time in case of both pathogens. Accordingly, B. bassiana and M. anisopliae were pathogenic on larvae of ELB.

Conclusions
The outputs of the study demonstrated that applications of these eco-friendly fungal pathogens with other non-chemical methods are recommended. Of course, under natural conditions, their efficiency may change; thus, more comprehensive studies are necessary.
Neurodegenerative disorders associated with genes of mitochondria
Authors: Marde Vaibhav S. , Tiwari Prerna L. , Wankhede Nitu L. , Taksande Brijesh G. , Upaganlawar Aman B. , Umekar Milind J. , Kale Mayur B. 
Published: March 2021

Abstract
Background
Over the last decade, aggregating evidences suggested that there is a causative link between mutation in gene associated with mitochondrial dysfunction and development of several neurodegenerative disorders.

Main text
Recent structural and functional studies associated with mitochondrial genes have shown that mitochondrial abnormalities possibly lead to mitochondrial dysfunction. Several studies on animal models of neurodegenerative diseases and mitochondrial genes have provided compelling evidence that mitochondria is involved in the initiation as well as progression of diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and Friedreich ataxia (FA).

Conclusion
In this mini-review, we have discussed the different etiologic and pathogenesis connected with the mitochondrial dysfunction and relevant neurodegenerative diseases that underlie the dominant part of mitochondrial genes in the disease development and its progress.