bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Dasatinib Vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized, Open-Label, Multicenter Study of the Chinese Children's Cancer Group
Authors: Shen Shuhong , Chen Xiaojuan , Cai Jiaoyang , Jie Yu , Gao Ju , HU Shaoyan , Zhai Xiaowen , Liang Changda , Ju Xiuli , Jiang Hua , Jin Runming , Wu Xuedong , Wang Ningling , Tian Xin , Pan Kaili , Jiang Hui , SUN Lirong , Fang Yongjun , Li Chi Kong , Hu Qun , Yang Minghua , Zhu Yiping , Li Chunfu , Yang Jun J. , Zhang Hui , Tang Jing-Yan , Zhu Xiaofan , Pui Ching-Hon
Published: February 2020

OBJECTIVE To determine whether dasatinib given at 80 mg/m2 is more effective than imatinib at 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL, in the context of intensive chemotherapy without prophylactic cranial irradiation.

DESIGN, SETTING, AND PARTICIPANTS This open-label phase III randomized study was conducted at 20 hospitals in China. Enrollment began in January 2015 and randomization was stopped in October 2018 when the early stopping criterion of the trial was met. Patients aged between 0 and 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined and 1 died before treatment.

INTERVENTIONS Patients were randomized to receive daily dasatinib (n=92) or imatinib (n=97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy.

MAIN OUTCOMES AND MEASURES The primary outcome was event-free survival, analyzed by intent-to-treat. The secondary outcomes were relapse, toxic death, and overall survival.

RESULTS With a median follow-up of 26.1 months (IQR 16.3-34.1), the 4-year event-free survival rate was 71.0% (95% CI 56.2-89.6) in the dasatinib group and 48.9% (95% CI 32.0-74.5, p=0.005) in the imatinib group (hazard ratio 2.36, 95% CI 1.27-4.40, p=0.007). The 4-year cumulative risk of any relapse was 19.8% (95% CI 4.2-35.4) in the dasatinib group and 34.4% (95% CI 15.6-53.2) in the imatinib group (p=0.01), while the 4-year cumulative risk of an isolated central-nervous-system relapse was 2.7% (95% CI 0.0-8.1) in the dasatinib group and 8.4% (95% CI -1.2-15.6) in the imatinib group (p=0.06). There were no significant differences in the frequency of severe toxicities between the two treatment groups.

CONCLUSION AND RELEVANCE Intensive chemotherapy including dasatinib at 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared to imatinib at 300 mg/m2 per day and provided excellent control of central-nervous-system leukemia without the use of prophylactic cranial irradiation.

Disclosures

No relevant conflicts of interest to declare.
Stat3-/- Alloreactive Donor T Cells Reduce FAO but Increase Leakage of ROS in Response to PD-1 Signaling Triggered By Host-Tissue PD-L1, Leading to Prevention of Gvhd While Preserving GVL Effect
Authors: Wang Xiaoqi , Yang Shijie , Wang Yating , Wu Xiwei , Salas Martha , Song Qingxiao , Qin Hanjun , Nasri Ubaydah , Riggs Arthur D. , Martin Paul J , Zhang Xi , Zeng Defu
Published: February 2020

The GVHD pathogenicity of alloreactive T cells is associated with enhanced glycolysis or enhanced fatty acid oxidation (FAO). PD-1 signaling in T cells inhibits glycolysis but augments FAO. Host tissue PD-L1 interaction with PD-1 on activated alloreactive T cells is not able to effectively prevent acute GVHD mediated by donor CD4+ and CD8+ T cells together, although it can reduce the severity of the disease. Using a murine HCT model of C57BL/6 donor to BALB/c recipient, we show that although WT T cells (CD4+ and CD8+ T cells together) induced lethal GVHD at 1-5 x106/mouse, the same dose of Stat3-/- donor T cells induced little signs of acute or chronic GVHD because of induction of T cell anergy, exhaustion and apoptosis, but with retention of a strong GVL effect. This induction of tolerance depends on donor T cell PD-1 interaction with host-tissue PD-L1, because Stat3-/- T cells induce severe lethal GVHD in the PD-L1-/- recipients and in WT recipients treated with blocking anti-PD-1 mAb. The tolerance of Stat3-/- donor T cells induced by PD-1 signaling is associated with lower FAO and mitochondria membrane potential (MMP) but higher ROS leakage, with little difference in glycolysis, as compared to non-tolerant WT T cells. In the absence of PD-1 signaling, Stat3-/- T cells manifest markedly enhanced glycolysis and loss of tolerance. These results indicate that activated donor T cell PD-1 interaction with host-tissue PD-L1 reduces glycolysis and reduces their GVHD capacity. In addition, absence of mitochondrial pStat3 in Stat3-/- donor T cells leads to reduced FAO and MMP but increased ROS leakage, resulting in effective anergy, exhaustion, and apoptosis of tissue infiltrating donor T cells and prevention of GVHD. At the same time, the reduced expression of PD-L1 in recipient lymphoid tissues allows donor T cell expansion and strong GVL activity. Our studies have revealed novel roles of mitochondria pStat3 in regulating PD-1 signaling, T cell metabolism and tolerance. (Grant support: R01AI066008 to Zeng) .

Disclosures

No relevant conflicts of interest to declare.
Structural Basis of Vitamin K Antagonism
Authors: Li Weikai , Liu Shixuan , Li Shuang
Published: February 2020

The vitamin K cycle supports blood coagulation, bone mineralization, and vascular calcium homeostasis. A key enzyme in this cycle, vitamin K epoxide reductase (VKOR), is the target of vitamin K antagonists (VKAs). Despite their extensive clinical use, the dose of VKAs (e.g., warfarin) is hard to regulate and overdose can lead to fatal bleeding. Improving the dose regulation requires understanding how VKAs inhibit VKOR, which is a membrane-embedded enzyme difficult to characterize with structural and biochemical studies. Here we achieve a long-standing goal of obtaining crystal structures of human VKOR with warfarin, which represents coumarin-based VKAs; with phenindione, which represents indandione-based VKAs; with superwarfarins, the most commonly used rodenticides; and with vitamin K epoxide in a reaction intermediate state. We have also solved structures of a VKOR-like homolog with warfarin, with vitamin K substrates, and without ligand. These structures show that human VKOR adopts an overall fold with four transmembrane helices (TM) and a large ER-luminal region. VKAs are bound at the active site of HsVKOR, which is formed by the surrounding four-TM bundle and a cap domain on top. The cap domain is stabilized by a linked anchor domain that interacts with the membrane surface. VKOR binds specifically to VKAs through hydrogen bonding to their diketone groups. Mutating VKOR residues recognizing the diketones render strong warfarin resistance. Except the hydrogen bonds, the binding pocket is largely hydrophobic. This pocket is incompatible with warfarin metabolite, explaining the inactivation of warfarin through CYP2C9 metabolism; CYP2C9 and VKOR genotypes can explain 30-50% of the patient variability in warfarin dose. In addition, the high potency of superwarfarins is due to the interaction of their side group with a tunnel where the isoprenyl chain of vitamin K is bound. For VKOR catalysis, the same residues affording the VKA-binding specificity also facilitate substrate reduction Initiation of the catalysis requires a reactive cysteine to form a substrate adduct. Interactions from this stably bound adduct induces a closed conformation, thereby triggering electron transfer to reduce the substrate. Importantly, the open to closed conformational change during catalysis similar to that induced by the binding of VKAs. Taken together, VKAs achieve inhibition through mimicking key interactions and conformational changes required for VKOR catalytic cycle. Understanding of these mechanisms will enable improved strategy to regulate warfarin dose and have a broad impact on thromboembolic diseases and bone disorders.

Disclosures

No relevant conflicts of interest to declare.
Prothrombin R541W Mutation Impairs Protein C Activation and Constitutes a New Genetic Risk Factor for Venous Thrombosis
Authors: WU XI , Jing Dai , Li Fang , Xu Qin , Chen Changming , Ding Qiulan , Wang Xuefeng , WU Wenman
Published: February 2020

Defective protein C (PC) pathway predisposes patients to venous thromboembolism (VTE)and is mostly, but not exclusively, attributed tohereditary PC or protein S (PS) deficiencies and activated PC resistance caused by factor V Leiden mutation. In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the three pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased. In conclusion, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin's procoagulant activity over anticoagulant function.

Figure

Disclosures

Ding: Shanghai General Hospital affiliated to Shanghai Jiao Tong University, Shanghai: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. Wang:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. WU:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work..
Regulation of eIF4E Guides a Unique Translational Program to Steer Erythroid Maturation
Authors: Forester Craig M , Woo-Byeon Gun , Oses-Prieto Juan , Burlingame Al , Barna Maria , Ruggero Davide M
Published: February 2020

Erythropoiesis is an intricately orchestrated process responsible for rapidly responding to an array of signaling cues to direct cell fates. While gene expression during erythropoiesis has mainly been studied at the transcription level, regulation of gene expression at the level of translation is still poorly understood. As translational control is one of the fastest steps to regulate protein abundance in the cell, we hypothesize that this mechanism plays an important role to rapidly control protein levels in response to extracellular cues during erythroid differentiation. However, outstanding questions remain on how translational control regulates specific gene programs in early erythroid states including 1.) how mRNA are selected for translation in normal erythropoiesis and 2.) how components of the translational machinery are regulated by upstream signaling pathways to orchestrate the translational landscape. In addressing these questions, we have nuncovered a dynamic interplay between Eukaryotic Initiation Factor 4E (eIF4E), the major mRNA cap binding protein that controls translation initiation and its repressor protein, 4EBP1 in erythropoiesis. Specifically, using in vivo phospho-flow cytometry analysis of the eIF4E-4EBP1 axis, eIF4E activity is high in early erythroid phases and is repressed by 4EBP1 in order to allow erythroid maturation. Surprisingly, high eIF4E activity in early erythroid precursors occurs without an increase in global protein synthesis. Utilizing a model of CD34+ human cord blood cells (HUDEP-2), we show that constitutive overexpression of eIF4E impaired erythropoietic maturation. To capture the specific proteins potentially regulated by eIF4E activity during erythropoiesis, we performed quantitative TMT mass spectrometry during HUDEP-2 erythroid differentiation. Our results revealed that eIF4E controls a specific key network of genes necessary for maintenance of early erythroid precursors. By analyzing the 5' untranslated region (5'UTR) of the eIF4E-dependent mRNA network, we identify a highly conserved, CT-rich motif which is required for these mRNAs to be more efficiently translated with increasing eIF4E levels. These results demonstrate wide-spread translational control of CT-rich mRNAs by eIF4E during early erythropoiesis. We are currently employing DMS-MaPseq to understand whether these motifs are also part of structured RNA elements that confer sensitivity to eIF4E levels. We have further extended these findings to a novel transgenic mouse model we have developed that allows in vivo assessment of increased eIF4E temporally at concise phases of erythroid maturation. Understanding this balance of eIF4E activity provides a novel insight into how of translational control dictates gene expression to determine phases of maturation in a crucial differentiation process.

Disclosures

No relevant conflicts of interest to declare.
Patients’ experiences of seeking help for emotional concerns in primary care: doctor as drug, detective and collaborator
Authors: Parker Daisy , Byng Richard , Dickens Chris , McCabe Rose
Published: February 2020

Background

NICE guidelines for the management of emotional concerns in primary care emphasise the importance of communication and a trusting relationship, which is difficult to operationalise in practice. Current pressures in the NHS mean that it is important to understand care from a patient perspective. This study aimed to explore patients’ experiences of primary care consultations for emotional concerns and what patients valued when seeking care from their GP.

Methods

Eighteen adults with experience of consulting a GP for emotional concerns participated in 4 focus groups. Data were analysed thematically.

Results

(1) Doctor as Drug: Patients’ relationship with their GP was considered therapeutic with continuity particularly valued. (2) Doctor as Detective and Validator: Patients were often puzzled by their symptoms, not recognising their emotional concerns. GPs needed to play the role of detective by exploring not just symptoms, but the person and their life circumstances. GPs were crucial in helping patients understand and validate their emotional concerns. (3) Doctor as Collaborator: Patients prefer a collaborative partnership, but often need to relinquish involvement because they are too unwell, or take a more active role because they feel GPs are ill-equipped or under too much pressure to help. Patients valued: GPs booking their follow up appointments; acknowledgement of stressful life circumstances; not relying solely on medication.

Conclusions

Seeking help for emotional concerns is challenging due to stigma and unfamiliar symptoms. GPs can support disclosure and understanding of emotional concerns by fully exploring and validating patients’ concerns, taking into account patients’ life contexts. This process of exploration and validation forms the foundation of a curative, trusting GP-patient relationship. A trusting relationship, with an emphasis on empathy and understanding, can make patients more able to share involvement in their care with GPs. This process is cyclical, as patients feel that their GP is caring, interested, and treating them as a person, further strengthening their relationship. NICE guidance should acknowledge the importance of empathy and validation when building an effective GP-patient partnership, and the role this has in supporting patients’ involvement in their care.
Information needs and information seeking behaviour of people with dementia and their non-professional caregivers: a scoping review
Authors: Soong Aijia , Au Shu Ting , Kyaw Bhone Myint , Theng Yin Leng , Tudor Car Lorainne
Published: February 2020

Background

People with dementia often require full-time caregivers especially in the later stages of their condition. People with dementia and caregivers’ access to reliable information on dementia is essential as it may have an important impact on patient care and quality of life. This study aims to provide an overview of the information needs and information seeking behaviour of people with dementia and their non-professional caregivers.

Methods

We conducted a scoping review of the literature and searched four electronic databases for eligible studies published up to August 2018. Two reviewers independently screened studies and extracted data. Information needs were classified according to emerging themes in the literature, and information seeking behaviour was categorized using Wilson’s model of information behaviour.

Results

Twenty studies with a total of 4140 participants, were included in this review. Reported information needs focused on: (i) disease; (ii) patient care provision; (iii) healthcare services; and (iv) caregiver self-care. The most commonly reported information need was on healthcare service-related information. Characteristics found to influence information needs were the severity of dementia as well as patient and caregiver status. People with dementia and non-professional caregivers mainly displayed active searching, information seeking behaviour and preferred using electronic sources to obtain health information.

Conclusion

Current dementia information sources available in English are extensive in the information they offer, but more emphasis needs to be placed on healthcare service-related information. All studies originated from high income countries and focused on information needs of non-professional caregivers only. The only variables found to be associated to information needs were severity of dementia condition as well as patient/caregiver status. The information needs identified in this review can be used to inform development and design of future dementia resources for people with dementia and their non-professional caregivers.
Nasogastric tube feeding versus assisted hand feeding in-home healthcare older adults with severe dementia in Taiwan: a prognosis comparison
Authors: Chou Hsiao-Hui , Tsou Meng-Ting , Hwang Lee-Ching
Published: February 2020

Background

All individuals with severe dementia should be offered careful hand feeding. However, under certain circumstances, people with severe dementia have a feeding tube placed. In Taiwan, tube feeding rate in demented older home care residents is increasing; however, the benefits of tube feeding in this population remain unknown. We compared the clinical prognosis and mortality of older patients with severe dementia receiving nasogastric tube feeding (NGF) or assisted hand feeding (AHF).

Methods

Data from the in-home healthcare system between January 1 and December 31, 2017 were analyzed to identify 169 participants over 60 years of age in this retrospective longitudinal study. All subjects with severe dementia and complete functional dependence suffered from difficulty in oral intake and required either AHF or NGF. Data were collected from both groups to analyze pneumonia, hospitalization, and mortality rates.

Results

A total of 169 subjects (56 males and 113 females, aged 85.9 ± 7.5 years) were analyzed. 39 required AHF and 130 NGF. All subjects were bedridden; 129 (76%) showed Barthel index < 10. Pneumonia risk was higher in the NGF group (48%) than in the AHF group (26%, p = 0.015). After adjusting for multiple factors in the regression model, the risk of pneumonia was not significantly higher in the NGF group compared with the AHF group. One-year mortality rates in the AHF and NGF groups were 8 and 15%, respectively, and no significant difference was observed after adjustment with logistic regression (aOR = 2.38; 95% CI, 0.58–9.70). There were no significant differences in hospitalization rate and duration.

Conclusions

For older patients with dementia requiring in-home healthcare, NGF is not associated with a significantly lower risk of pneumonia than AHF. Additionally, neither mortality nor hospitalization rates decreased with NGF. On the contrary, a nonsignificant trend of increased risk of pneumonia was observed in NGF group. Therefore, the benefits of NGF are debatable in older patients with severe dementia requiring in-home healthcare. Continued careful hand feeding could be an alternative to NG feeding in patients with severe dementia. Furthermore, large-scale studies on in-home healthcare would be required to support these results.
A post-market, multi-vessel evaluation of the imaging of peripheral arteries for diagnostic purposeS comparing optical Coherence tomogrApy and iNtravascular ultrasound imaging (SCAN)
Authors: Pavillard Edward , Sewall Luke
Published: February 2020

Background

Intravascular imaging plays an important part in diagnosis of vascular conditions and providing insight for treatment strategy. Two main imaging modalities are intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The objective of this study was to prove non-inferiority of OCT imaging to IVUS images in matched segments of peripheral vessels in patients with suspected peripheral vascular disease.

Methods

The SCAN study was a prospective, non-inferiority clinical study of matched IVUS and OCT images collected along defined segments of peripheral vessels from twelve subjects (mean age 68 ± 10.3 years; 10 men) displaying symptoms of vascular disease. Luminal diameters were measured by both imaging systems at the distal, middle, and proximal points of the defined segments. Three blinded interventional radiologists evaluated the quality of both imaging modalities in identifying layered structures (3-point grading), plaque (5-point grading), calcification (5-point grading), stent structure (3-point grading), and artifacts (3-point grading) from 240 randomly ordered images. Mean grading scores and luminal diameters were calculated and analyzed with Student’s t-Test and Mann-Whitney-Wilcoxon testing. Intrareader reproducibility was calculated by intraclass correlation (ICC) analysis.

Results

The mean scoring of plaque, calcification, and vascular stent struts by the three readers was significant better in terms of image quality for OCT than IVUS (p < 0.001,p = 0.001,p = 0.004, respectively). The mean scores of vessel wall component visibility and artifacts generated by the two imaging systems were not significantly different (p = 0.19,p = 0.07, respectively). Mean vessel luminal diameter and area at three specific locations within the vessels were not significantly different between the two imaging modalities. No patient injury, adverse effect or device malfunction were noted during the study.

Conclusions

Imaging by OCT provides the physician with better visualization of some vessel and plaque chacteristics, but both IVUS and OCT imaging are safe and effective methods of examining peripheral vessels in order to perform diagnostic assessment of peripheral vessels and provide information necessary for the treatment strategy of peripheral artery disease.

Trial registration

NCT03480685registered on 29 March 2018.
Low dose of flurbiprofen axetil decrease the rate of acute kidney injury after operation: a retrospective clinical data analysis of 9915 cases
Authors: Wang Dong , Yang Shi-Kun , Zhao Meng-Xi , Tang Yong-Zhong , OU-Yang Wen , Zhang Hao , Liao Qin
Published: February 2020

Background

Flurbiprofen axetil (FA) is a commonly prescribed agent to relieve perioperative pain, but the relationship between FA and postoperative acute kidney injury (AKI) remains unclear. This study attempted to evaluate the effects of different dose of perioperative FA on postoperative AKI.

Methods

A total of 9915 patients were enrolled for this retrospective study. The clinical characteristics and the prevalence of postoperative AKI among patients non-using, using low dose (50-100 mg), middle dose (100-250 mg) and large dose (≧250 mg) of FA were analyzed respectively. The impact of different dose of FA on postoperative AKI was analyzed using univariable and multivariate logistic regression analysis.

Results

The prevalence of postoperative AKI was 6.7% in the overall subjects and 5.1% in 2446 cases who used FA. The incidence of AKI in low dose group was significantly less than that of non use group (4.5% vs 7.2%,P < 0.001), but the incidence of AKI in large dose group was significantly higher than that in the non-use group (18.8% vs 7.2%,P < 0.001). However, there was no significant difference between patients without using FA and subjects using middle dose of FA (7.2% vs 5.6%,p = 0.355). Multivariate logistic regression analysis showed that low dose of FA was a protective factor for postoperative AKI (OR = 0.75,p = 0.0188), and large dose of FA was a risk factor for postoperative AKI (OR = 4.8,p < 0.0001).

Conclusions

The impact of FA on postoperative AKI was dose-dependent, using of low dose FA (50-100 mg) perioperatively may effectively reduce the incidence of postoperative AKI.
Capacity and patient flow planning in post-term pregnancy outpatient clinics: a computer simulation modelling study
Authors: Viana Joe , Simonsen Tone Breines , Faraas Hildegunn E. , Schmidt Nina , Dahl Fredrik A. , Flo Kari
Published: February 2020

Background

The demand for a large Norwegian hospital’s post-term pregnancy outpatient clinic has increased substantially over the last 10 years due to changes in the hospital’s catchment area and to clinical guidelines. Planning the clinic is further complicated due to the high did not attend rates as a result of women giving birth. The aim of this study is to determine the maximum number of women specified clinic configurations, combination of specified clinic resources, can feasibly serve within clinic opening times.

Methods

A hybrid agent based discrete event simulation model of the clinic was used to evaluate alternative configurations to gain insight into clinic planning and to support decision making. Clinic configurations consisted of six factors: X0: Arrivals. X1: Arrival pattern. X2: Order of midwife and doctor consultations. X3: Number of midwives. X4: Number of doctors. X5: Number of cardiotocography (CTGs) machines. A full factorial experimental design of the six factors generated 608 configurations.

Results

Each configuration was evaluated using the following measures: Y1: Arrivals. Y2: Time last woman checks out. Y3: Women’s length of stay (LoS). Y4: Clinic overrun time. Y5: Midwife waiting time (WT). Y6: Doctor WT. Y7: CTG connection WT. Optimisation was used to maximise X0 with respect to the 32 combinations of X1-X5. Configuration 0a, the base case Y1 = 7 women and Y3 = 102.97 [0.21] mins. Changing the arrival pattern (X1) and the order of the midwife and doctor consultations (X2) configuration 0d, where X3, X4, X5 = 0a, Y1 = 8 woman and Y3 86.06 [0.10] mins.

Conclusions

The simulation model identified the availability of CTG machines as a bottleneck in the clinic, indicated by the WT for CTG connection effect on LoS. One additional CTG machine improved clinic performance to the same degree as an extra midwife and an extra doctor. The simulation model demonstrated significant reductions to LoS can be achieved without additional resources, by changing the clinic pathway and scheduling of appointments. A more general finding is that a simulation model can be used to identify bottlenecks, and efficient ways of restructuring an outpatient clinic.
Detection of fowl adenovirus D strains in wild birds in Poland by Loop-Mediated Isothermal Amplification (LAMP)
Authors: Niczyporuk Jowita Samanta , Kozdruń Wojciech , Czekaj Hanna , Styś-Fijoł Natalia , Piekarska Karolina
Published: February 2020

Background

The present study on the role of strains of adenovirus in wildlife reservoirs, and their prevalence is under exploration. In several previous studies, the presence of adenovirus strains in wild birds has been investigated. Worldwide distribution and outbreaks of adenovirus infections have been reported by many authors. The present study investigated the prevalence of FAdVs in 317 samples of different bird species from the northwestern region of Poland. An applied specific, sensitive, and efficient, without cross-reactivity loop-mediated isothermal amplification (LAMP) method to gauge the prevalence of fowl adenovirus strains in wild birds was developed and used.

Results

The method was based on the sequence of the loop L1 HVR1–4 region of the hexon gene of the FAdV genome reference strains FAdV-2 KT862805 (ANJ02325), FAdV-3 KT862807 (ANJ02399) and FAdV-11 KC750784 (AGK29904). The results obtained by LAMP were confirmed by real-time PCR. Among 317 samples obtained from wild birds, eight FAdV isolates (2.52%) were identified and produced a cytopathic effect (CPE) in chicken embryo kidney cells (CEK). Three FAdV types belonging to species Fowl adenovirus D were detected, which were isolated from three adenovirus types 2/3/11, and have been confirmed in three mute swans (Cygnus olor), three wild ducks (Anas platyrhynchos), one owl (Strigiformes), and one common wood pigeon (Columba palumbus).

Conclusions

This study provides the first accurate quantitative data for the replication of fowl adenovirus strains in wild birds in Poland, indicating adenovirus interspecies transmission, and demonstrating the circulation of FAdVs in wild birds.
A bioanalytical UHPLC based method used for the quantification of Thymoquinone-loaded-PLGA-nanoparticles in the treatment of epilepsy
Authors: Ahmad Niyaz , Ahmad Rizwan , Al Qatifi Sadiq , Alessa Mahdi , Al Hajji Hassan , Sarafroz Md
Published: February 2020

To formulate a nanoformulation (PLGA-NPs) and to improve brain bioavailability for thymoquinone (THQ) through intranasal (i.n.) drug delivery, using a newly UHPLC-PDA developed the method and validated. Five different THQ-PLGA-NPs (THQ-N1 to THQ-N5) were prepared by emulsion solvent evaporation method. A new UHPLC method developed and validated for biodistribution studies in the rat’s brain, lungs and plasma. Optimized-THQ-N1-NPs showed a particle size of 97.36 ± 2.01 nm with a low PDI value of 0.263 ± 0.004, ZP of − 17.98 ± 1.09, EE of 82.49 ± 2.38% and DL of 5.09 ± 0.13%. THQ-N1-NPs showed sustained release pattern via in vitro release profile. A bioanalytical method was developed by UHPLC-PDA and validated for the evaluation of pharmacokinetics parameters, biodistribution studies, brain drug-targeting potential (89.89 ± 9.38%), and brain-targeting efficiency (8075.00 ± 113.05%) studies through intranasal administration which showed an improved THQ-brain- bioavailability, compared to i.v. Moreover, THQ-PLGA-NPs improved the seizure threshold treatment i.e. epilepsy increasing current electroshock (ICES) rodent models induced seizures in rats. A significant role of THQ-PLGA-NPs with high brain targeting efficiency of the nanoformulations was established. The reported data supports the treatment of epilepsy.
Pastoral community practices, microbial quality and associated health risks of raw milk in the milk value chain of Nakasongola District, Uganda
Authors: Majalija Samuel , Tumwine Gabriel , Kiguli Juliet , Bugeza James , Ssemadaali Marvin Apollo , Kazoora Hebert Brian , Namukose Muwanguzi Esther , Nantima Noelina , Tuyiragize Richard
Published: February 2020

The informal milk value chain in Uganda controls most of the raw marketed milk, albeit of poor quality. A study was conducted to assess the milk handling practices, the bacterial quality and the associated health concerns of raw milk along the informal milk value in Nakasongola District. The cross-sectional study used both qualitative and quantitative methods to obtain information from key players. The qualitative data was categorized and presented into emerging themes. Bacterial contamination of 200 milk samples was determined by morphological and biochemical tests. The antibiotic susceptibility test was done by the disc diffusion method.

Hand milking was carried out mainly by men (92.5%), and most never or rarely practised hand washing (67.5%) during milking. Milk was mainly delivered to mobile milk-collecting centres located under tree shades (50%). The quality of raw milk was affected by poor hygienic, handling and transportation practices. Most participants (75%) were aware of the dangers of drinking raw milk and the requirements to transport milk in metallic cans. Viable bacterial counts above the recommended limit were recorded in 76 samples (38%) that included Staphylococcus aureus (46%), coagulase-negative Staphylococcus (29%), Escherichia coli (12%), Streptococcus agalactiae (8%) and Salmonella spp. (5%). The overall antibiotic resistance was 45% (34/76), which included resistant isolates of S. aureus (17/34), coagulase-negative Staphylococcus (11/22), S. agalactiae (3/6), Salmonella spp. (2/4) and E. coli (2/9).

The raw milk contaminated with antibiotic drug-resistant bacterial pathogens is of public health concern. Thus, measures to improve the quality of milk need to be designed for the pastoral community in Nakasongola district.
Clearcuts and related secondary dieback undermine the ecological effectiveness of FSC certification in a boreal forest
Authors: Blumröder Jeanette Silvin , Hoffmann Monika T. , Ilina Olga , Winter Susanne , Hobson Peter R. , Ibisch Pierre L.
Published: February 2020

Background

Over the last 25 years, the prominent forest certification system established by the Forest Stewardship Council (FSC) has used by many companies worldwide for claiming responsible forest management. The objectives of the Russian National FSC standard to decrease the size of clearcuts and the retention of forest elements such as residual seed trees need on-site validation to proof the effectiveness of FSC. To assess the ecological impacts of harvesting practices and benefits of FSC certification, we geospatially compared logging activities with and without FSC certification. Within a sample area covering approximately 3,000 km2 in the east of the Russian Arkhangelsk Region, we used available data on tree cover loss and satellite images to assess secondary impacts of clearcuttings on adjacent remnant forests and to quantify the logging intensity. Additionally, the size and structure as well as the density of skidding trails of ten specific clearcuttings located within the sample area were surveyed using satellite images and in the field observation to delineate the boundaries of clearcuts and forested remnants within the clearcuts.

Results

We found a significant increase of small-scale tree cover loss in the proximity of the clearcuts. Patchy dieback is possibly linked to the scale and intensity of logging in the surroundings. On the investigated clearcuts, FSC failed to reduce the size, to increase the retention of forest remnants including seed trees on logged areas, and to maintain larger tracts of undisturbed ground and soil compared to clearcuts that were logged before they received FSC-certification.

Conclusions

Trees and forest remnants remaining inside an increasingly stressed forest ecosystem matrix may not resist further harvesting-related and climate change-induced stresses and disturbances. Large-scale clearcuttings seem to have negative impacts even in adjacent forests and undermine the ecological effectiveness of FSC certification in the study area. The Russian FSC standard is not clearly setting effective guidelines that induce a change in clearcutting practices in order to reduce ecological risks.
Domestication of Oryza species eco-evolutionarily shapes bacterial and fungal communities in rice seed
Authors: Kim Hyun , Lee Kiseok Keith , Jeon Jongbum , Harris William Anthony , Lee Yong-Hwan
Published: February 2020

Background

Plant-associated microbiomes, which are shaped by host and environmental factors, support their hosts by providing nutrients and attenuating abiotic and biotic stresses. Although host genetic factors involved in plant growth and immunity are known to shape compositions of microbial communities, the effects of host evolution on microbial communities are not well understood.

Results

We show evidence that both host speciation and domestication shape seed bacterial and fungal community structures. Genome types of rice contributed to compositional variations of both communities, showing a significant phylosymbiosis with microbial composition. Following the domestication, abundance inequality of bacterial and fungal communities also commonly increased. However, composition of bacterial community was relatively conserved, whereas fungal membership was dramatically changed. These domestication effects were further corroborated when analyzed by a random forest model. With these changes, hub taxa of inter-kingdom networks were also shifted from fungi to bacteria by domestication. Furthermore, maternal inheritance of microbiota was revealed as a major path of microbial transmission across generations.

Conclusions

Our findings show that evolutionary processes stochastically affect overall composition of microbial communities, whereas dramatic changes in environments during domestication contribute to assembly of microbiotas in deterministic ways in rice seed. This study further provides new insights on host evolution and microbiome, the starting point of the holobiome of plants, microbial communities, and surrounding environments.
A question is “what are the optimal targets for anticoagulant therapies?”
Authors: Yokoyama Nobuyuki , Takaki Shunsuke , Yokose Masashi , Kuwabara Kaori , Anzai Akiko , Hamada Takako , Kashiwagi Shizuka , Okamura Kenta , Sugawara Yoh , Goto Takahisa
Published: February 2020

A high mortality rate is found among septic patients with disseminated intravascular coagulation (DIC). Anticoagulants have been used for treating septic DIC especially in Japanese clinical settings; however, their effectiveness is quite controversial across studies. According to several randomized controlled trials and meta-analyses, antithrombin and recombinant thrombomodulin had no therapeutic benefit in the treatment of sepsis. However, the majority of the previous research did not discuss “septic DIC” but simply “sepsis”, and some reviews showed that anticoagulants were benefit only in septic DIC. Although immunothrombosis plays an important role in early host defense, it can lead to DIC and organ failure if dysregulated. Therefore, we advocate anticoagulant therapies might have beneficial effects, but research on optimal patient selection is currently lacking.
Differences in anticoagulation strategy and outcome in atrial fibrillation patients with chronic kidney disease: a CODE-AF registry study
Authors: Choi Yeon-Jik , Uhm Jae-Sun , Kim Tae-Hoon , Cha Myung-Jin , Lee Jung Myung , Park Junbeom , Park Jin-Kyu , Kang Ki-Woon , Shim Jaemin , Kim Jun , Park Hyung Wook , Choi Eue-Keun , Kim Jin-Bae , Kim Changsoo , Lee Young Soo , Joung Boyoung
Published: February 2020

Purpose

Dose reduction of non-vitamin K antagonist oral anticoagulants (NOACs) is indicated in patients with atrial fibrillation (AF) with renal impairment. This study investigated anticoagulation patterns and outcomes in patients with chronic kidney disease (CKD).

Materials and methods

In a prospective observational registry (CODE-AF), 3445 patients with non-valvular AF including 1129 with CKD (estimated glomerular filtration rate ≤ 60 mL min−1 1.73 m−2) were identified between June 1, 2016, and July 3, 2017.

Results

Compared with patients with no-CKD, patients with CKD more frequently had a high stroke risk (94.9% vs. 67.0%,p < 0.001) and higher NOAC usage rate (61.1% vs. 47.8%,p < 0.001). Among 718 patients with renal indication for dose reduction (RIDR), 7.5% were potentially overdosed. Among 2587 patients with no-RIDR, 79% were potentially underdosed. Compared with patients with no-RIDR, the underdose rates of dabigatran (0% vs. 88.6%,p = 0.001) and rivaroxaban (0% vs. 79.5%,p = 0.001) were lower in patients with RIDR. However, the underdose rate of apixaban was not different (62.5% vs. 53.9%,p = 0.089). The overdose rate of dabigatran (7.5% vs. 0%) and rivaroxaban (13.7% vs. 0%) was higher in RIDR than in no-RIDR patients. Stroke/transient ischemic attack was significantly higher in CKD patients (1.4 vs. 0.6 per 100 person-years,p = 0.045). Aspirin significantly increased minor bleeding in CKD patients compared with controls (p = 0.037).

Conclusion

CKD patients might have a high stroke risk and NOAC usage rate. The underdose rate of NOACs decreased in CKD patients, except for apixaban. Aspirin significantly increased minor bleeding in CKD patients.
Estimation model of winter wheat disease based on meteorological factors and spectral information
Authors: Li Weiguo , Liu Yang , Chen Hua , Zhang Cheng Cheng
Published: February 2020

Wheat scab (WS, Fusarium head blight), one of the most severe diseases of winter wheat in Yangtze-Huaihe river region, whose monitoring and timely forecasting at large scale would help to optimize pesticide spraying and achieve the purpose of reducing yield loss. In the present study, remote sensing monitoring on WS was conducted in 4 counties in Yangtze-Huaihe river region. Sensitive factors of WS were selected to establish the remote sensing estimation model of winter wheat scab index (WSI) based on interactions between spectral information and meteorological factors. The results showed that: 1) Correlations between the daily average temperature (DAT) and daily average relative humidity (DAH) at different time scales and WSI were significant. 2) There were positive linear correlations between winter wheat biomass, leaf area index (LAI), leaf chlorophyll content (LCC) and WSI. 3) NDVI (normalized difference vegetation index), RVI (ratio vegetation index) and DVI (difference vegetation index) which had a good correlation with LAI, biomass and LCC, respectively, and could be used to replace them in modeling. 4) The estimated values of the model were consistent with the measured values (RMSE = 5.3%, estimation accuracy = 90.46%). Estimation results showed that the model could efficiently estimate WS in Yangtze-Huaihe river region.

Graphical abstract
The asymptotic local finite-difference method of the fractional wave equation and its viscous seismic wavefield simulation
Authors: Song Guojie , Zhang Xinmin , Wang Zhiliang , Chen Yali , Chen Puchun
Published: February 2020

Viscous seismic wave propagation simulation using the fractional order equation has attracted much recent attention. However, conventional finite-difference (FD) methods of the fractional partial difference equation adopt a global difference operator to approximate the fractional derivatives, which reduces the computational efficiency dramatically. To improve the efficiency of the FD method, we have developed a reasonable truncated stencil pattern by strict mathematical derivation and adopted an asymptotic local FD (ALFD) method. Theoretical analysis and numerical results indicate that the ALFD method is accurate and efficient. In fact, our numerical results illustrate that the numerical solution solved by the ALFD method has a maximum relative error not exceeding 0.014% compared to the reference solution (applied to a finely meshed computational domain). The computation speed of ALFD is also significantly faster than that of the original FD method. The computational time of the three ALFD methods satisfying a different preset accuracy is only approximately 2.71%, 1.26%, and 0.78% of that of the original fractional wave equation FD method. The ALFD method provides a useful tool for viscoelastic seismic wavefield propagation simulation.
Sedimentary characteristics and mechanism analysis of a large-scale fan delta system in the Paleocene Kongdian Formation, Southwestern Bohai Sea, China
Authors: Du Xiaofeng , Wang Qiming , Zhao Meng , Liu Xiaojian
Published: February 2020

Exploration of the deep buried sandstones and glutenites of the Paleocene Kongdian Formation of the Bozhong 19-6 structure was a significant success. An integrated analysis of 3D seismic data, logging curves, core observation, thin sections, and casting thin sections was applied to characterize the sequences, petrology, sedimentary facies, and reservoir properties of the glutenite of the Kongdian Formation. The results indicated that the Kongdian Formation mainly consisted of tuffaceous glutenites at the lower section and glutenites in the upper section. The porosities ranged from 0.3% to 17.7%, whereas the permeability ranged from 0.0175 to [Formula: see text], indicating ultralow porosity and ultralow permeability reservoir characteristics. The northern source area, the Chengbei Low Uplift in the west, and the Bonan Low Uplift in the southeast surrounded the Bozhong 19-6 structure and provided abundant proximal coarse-grained sediments for a large-scale fan delta system. The paleogeography, slope type, parent rock type, and lake-level changes were the key factors controlling the glutenite reservoirs. The paleogeography reconstructed by prototype basin analysis controlled the southward-thickening sedimentation pattern of the glutenite. The slope type controlled the multistage development of the glutenite. The parent rock controlled the reservoir quality. The lake-level cycle controlled the stacking pattern of the glutenite. The successful gas discovery in the Bozhong 19-6 structure suggests that the deep buried fan delta system of the Kongdian Formation could have great petroleum potential for future exploration of the Bohai Bay Basin.
Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001
Authors: Brown Paul D. , Gondi Vinai , Pugh Stephanie , Tome Wolfgang A. , Wefel Jeffrey S. , Armstrong Terri S. , Bovi Joseph A. , Robinson Cliff , Konski Andre , Khuntia Deepak , Grosshans David , Benzinger Tammie L. S. , Bruner Deborah , Gilbert Mark R. , Roberge David , Kundapur Vijayananda , Devisetty Kiran , Shah Sunjay , Usuki Kenneth , Anderson Bethany Marie , Stea Baldassarre , Yoon Harold , Li Jing , Laack Nadia N. , Kruser Tim J. , Chmura Steven J. , Shi Wenyin , Deshmukh Snehal , Mehta Minesh P. , Kachnic Lisa A. ,   for NRG Oncology
Published: February 2020

PURPOSE

Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition.

METHODS

This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden.

RESULTS

Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01).

CONCLUSION

HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.