bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of 3D-Printed Polycaprolactone-/Polyvinylpyrrolidone-Based Constructs
Authors: Izgordu Muhammet Sefa , Uzgur Evren Isa , Ulag Songul , Sahin Ali , Karademir Yilmaz Betul , Kilic Beyhan , Ekren Nazmi , Oktar Faik Nuzhet , Gunduz Oguzhan
Published: January 2020

The aim of this study is to evaluate the mechanical and biological performance of cartilage-like constructs produced by 3D printing. During the investigation, poly(ε-caprolactone) (PCL) and polyvinylpyrrolidone (PVP) were used as a matrix polymer and low-molecular-weight chitosan (CS), hyaluronic acid (HA), and alginic acid sodium salt (SA) were integrated separately with the polymer matrix to fabricate the constructs. Thermal, mechanical, morphology, and chemical properties and swelling, degradation, and biocompatibility behaviors were evaluated in detail. With the addition of 3 fillers, the melting temperature of the matrix increased with the addition of fillers, and PCL/3wt.%PVP/1wt.%HA had the highest melting temperature value. Mechanical characterization results demonstrated that the printed PCL/3wt.%PVP/1wt.%CS displayed the highest compressive strength of around 9.51 MPa. The compressive strength difference between the PCL/3wt.%PVP and PCL/3wt.%PVP/1wt.%CS was 5.38 MPa. Biocompatibility properties of the constructs were tested by mitochondrial dehydrogenase activity, and in vitro studies showed that the PCL/3wt.%PVP/1wt.%HA composite construct had more cell viability than the other constructs by making use of the mesenchymal stem cell line.
First report of Lyme borreliosis leading to cardiac bradydysrhythmia in two cats
Authors: Tørnqvist-Johnsen Camilla , Dickson Sara-Ann , Rolph Kerry , Palermo Valentina , Hodgkiss-Geere Hannah , Gilmore Paul , Gunn-Moore Danièlle A
Published: January 2020

Case series summary

Two cats were presented for investigation of bradyarrhythmia detected by their referring veterinarians during routine examination. Both cats had extensive investigations, including haematology, serum biochemistry with electrolytes and thyroxine concentrations, systolic blood pressure measurement, echocardiography, electrocardiography and infectious disease testing. Infectious disease testing included serology for Toxoplasma gondii, Ehrlichia canis, Anaplasma phagocytophilum and Borrelia burgdorferi, and PCR for B burgdorferi antigen in both cats. Case 1 was also assessed by PCR for Bartonella henselae antigen and case 2 was assessed for Dirofilaria immitis by serology. All infectious disease tests, other than for B burgdorferi, were negative. Case 1 was diagnosed with Lyme carditis based on marked bradydysrhythmia, positive B burgdorferi serology, a structurally normal heart and clinical resolution with appropriate treatment with a 4-year follow-up. Case 2 was diagnosed with Lyme carditis based on marked bradydysrhythmia and positive B burgdorferi PCR; however, this cat had structural heart disease that did not resolve with treatment.

Relevance and novel information

This small case series describes two B burgdorferi positive cats presenting with newly diagnosed cardiac abnormalities consistent with those found in humans and dogs with Lyme carditis. Both cats were asymptomatic as perceived by their owners; the arrhythmia was detected by their veterinarians.
Glycosaminoglycans from Co-Products of «Scyliorhinus canicula»: Extraction and Purification in Reference to the European Pharmacopoeia Requirement
Authors: Talmoudi Nawras , Ghariani Noureddine , Sadok Saloua
Published: January 2020

Background

Glycosaminoglycans (GAGs), including hyaluronic acid (HA), dermatan sulfate (DS) and chondroitin sulfate (CS) are essential components of the bone and cartilage tissues. CS isolated from the cartilage tissue of various animals has found application in pharmaceuticals, cosmetics and food industries. In the first part of the present work, three methods were used and compared to extract and purify glycosaminoglycans (GAGs) from the cartilage powder of a local cartilaginous marine species «Scyliorhinus canicula». One of these GAGs, chondroitin sulfate (CS), will be exploited for the development of an anti-osteoarthritis generic at the request of a collaborative pharmaceutical industry. Thus this active ingredient must meet the requirements and tests described by the European Pharmacopoeia (Ph. Eur.). These tests are treated in the second part of this work.

Results

Among the three methods that have been applied in the present work, in order to optimize the best process for GAGs preparation, enzymatic hydrolysis with papain followed by deproteinisation using trichloroacetic acid (TCA) was found the best one. The separation of the extracted GAGs using agarose gel electrophoresis, and the identification of bands by Fourier Transform Infrared (FT-IR) Spectroscopy, revealed that the cartilage GAGs of« Scyliorhinus canicula»are exclusively chondroitin sulfate (CS) and dermatane sulfate (DS), with proportions of 12.889 and 87.111% respectively, and that CS is of type C. The extraction technique with papain provides a product with GAGs content of around 90%. The TCA deproteinisation yielded the lowest level of protein (2.8%) in the extracted GAGs, less than 3%, which is the standard required by the European Pharmacopoeia (Ph. Eur.).

Cetylpyridinium chloride (CPC) assay suggests that the titration technique, although is introduced by the Ph. Eur. for the determination of CS content, is not an accurate method, and that the values obtained by the optimized and validated HPLC method, described in this work, are more exact.

Conclusion

The extracted and purified active ingredient is perfectly conform to the tests described by the Ph. Eur. The results suggest that the co-product ofScyliorhinus caniculawould be a perfect source of molecules of pharmacological interest, obtained by a simple and non-agressive process.
The 2011 break in the part-time indicator and the evolution of wage inequality in Germany
Authors: Fitzenberger Bernd , Seidlitz Arnim
Published: January 2020

German social security records involve an indicator for part-time or full-time work. In 2011, the reporting procedure was changed suggesting that a fraction of worker recorded to be working full-time before the change were in fact part-time workers. This study develops a correction based on estimating the probability of being a part-time worker before and after the break. Using the correction, the paper confirms that the rise in wage inequality among full-time workers in West Germany until 2010 is not a spurious consequence of the misreporting of working time.
Reconstruction and analysis of a carbon-core metabolic network for Dunaliella salina
Authors: Fachet Melanie , Witte Carina , Flassig Robert J. , Rihko-Struckmann Liisa K. , McKie-Krisberg Zaid , Polle Jürgen E. W. , Sundmacher Kai
Published: January 2020

Background

The green microalga Dunaliella salina accumulates a high proportion of β-carotene during abiotic stress conditions. To better understand the intracellular flux distribution leading to carotenoid accumulation, this work aimed at reconstructing a carbon core metabolic network for D. salina CCAP 19/18 based on the recently published nuclear genome and its validation with experimental observations and literature data.

Results

The reconstruction resulted in a network model with 221 reactions and 212 metabolites within three compartments: cytosol, chloroplast and mitochondrion. The network was implemented in the MATLAB toolbox and checked for feasibility. Furthermore, a flux balance analysis was carried out for different light and nutrient uptake rates. The comparison of the experimental knowledge with the model prediction revealed that the results of the stoichiometric network analysis are plausible and in good agreement with the observed behavior. Accordingly, our model provides an excellent tool for investigating the carbon core metabolism of D. salina.

Conclusions

The reconstructed metabolic network of D. salina presented in this work is able to predict the biological behavior under light and nutrient stress and will lead to an improved process understanding for the optimized production of high-value products in microalgae.
Global scale transcriptome analysis reveals differentially expressed genes involve in early somatic embryogenesis in Dimocarpus longan Lour
Authors: Chen Yukun , Xu Xiaoping , Liu Zhuanxia , Zhang Zihao , XuHan Xu , Lin Yuling , Lai Zhongxion
Published: January 2020

Background

Somatic embryogenesis (SE) is a process of somatic cells that dedifferentiate to totipotent embryonic stem cells and generate embryos in vitro. Longan SE has been established and wildly used as model system for studying embryogenesis in woody plants, SE-related genes had been characterized. In spite of that, a comprehensive overview of SE at a molecular level is still absent. To understand the molecular mechanisms during longan SE, we examined the transcriptome changes by using Illumina HiSeq from the four distinct developmental stages, including non-embryogenic callus (NEC), embryogenic callus (EC), incomplete compact pro-embryogenic cultures (ICpEC), globular embryos (GE).

Results

RNA-seq of the four samples generated a total of 243.78 million high quality reads, approximately 81.5% of the data were mapped to longan genome. The cDNA libraries of NEC, EC, ICpEC and GE, generated 22,743, 19,745, 21,144, 21,102 expressed transcripts, 1935, 1710, 1816, 1732 novel transcripts, 2645, 366, 505, 588 unique genes, respectively. Comparative transcriptome analysis showed that a total of 10,642, 4180, 5846 and 1785 genes were differentially expressed in the pairwise comparisons of NEC_vs_EC, EC_vs_ICpEC, EC_vs_GE, ICpEC_vs_GE, respectively. Among them, plant hormones signalling related genes were significantly enriched, especially the auxin and cytokinin signalling components. The transcripts of flavonoid biosynthesis related genes were mainly expressed in NEC, while fatty acid biosynthesis related genes mainly accumulated in early SE. In addition, the extracelluar protein encoding genesLTP,CHI,GLP,AGP,EP1were related to longan SE. Combined with the FPKM value of longan nine tissues transcription, 27 SE specific or preferential genes (LEC1,LEC1-like,PDF1.3,GH3.6,AGL80,PIN1,BBM,WOX9,WOX2,ABI3, et al.) and 28 NEC preferential genes (LEA5,CNOT3,DC2.15,PR1–1,NsLTP2,DIR1,PIP1,PIP2.1,TIP2–1,POD-P7andPOD5et al.) were characterized as molecular markers for longan early SE. qRT-PCR validation of SE-related genes showed a high correlation between RNA-seq and qRT-PCR data.

Conclusion

This study provides new insights into the role of the transcriptome during early SE in longan. Differentially expressed genes reveal that plant hormones signalling, flavonoid and fatty acid biosynthesis, and extracelluar protein related genes were involved in longan early SE. It could serve as a valuable platform resource for further functional studies addressing embryogenesis in woody plants.
Analysis of MADS-box genes revealed modified flowering gene network and diurnal expression in pineapple
Authors: Zhang Xiaodan , Fatima Mahpara , Zhou Ping , Ma Qing , Ming Ray
Published: January 2020

Background

Pineapple is the most important crop with CAM photosynthesis, but its molecular biology is underexplored. MADS-box genes are crucial transcription factors involving in plant development and several biological processes. However, there is no systematic analysis of MADS-box family genes in pineapple (Ananas comosus).

Results

Forty-eight MADS-box genes were identified in the pineapple genome. Based on the phylogenetic studies, pineapple MADS-box genes can be divided into type I and type II MADS-box genes. Thirty-four pineapple genes were classified as type II MADS-box genes including 32 MIKC-type and 2 Mδ-type, while 14 type I MADS-box genes were further divided into Mα, Mβ and Mγ subgroups. A majority of pineapple MADS-box genes were randomly distributed across 19 chromosomes. RNA-seq expression patterns of MADS-box genes in four different tissues revealed that more genes were highly expressed in flowers, which was confirmed by our quantitative RT-PCR results. There is no FLC and CO orthologs in pineapple. The loss of FLC and CO orthologs in pineapple indicated that modified flowering genes network in this tropical plant compared with Arabidopsis. The expression patterns of MADS-box genes in photosynthetic and non-photosynthetic leaf tissues indicated the potential roles of some MADS-box genes in pineapple CAM photosynthesis. The 23% of pineapple MADS-box genes showed diurnal rhythm, indicating that these MADS-box genes are regulated by circadian clock.

Conclusions

MADS-box genes identified in pineapple are closely related to flowering development. Some MADS-box genes are involved in CAM photosynthesis and regulated by the circadian clock. These findings will facilitate research on the development of unusual spiral inflorescences on pineapple fruit and CAM photosynthesis.
Post-lingual non-syndromic hearing loss phenotype: a polygenic case with 2 biallelic mutations in MYO15A and MITF
Authors: Khalil Athar , Karroum Samer Bou , Barake Rana , Dunya Gabriel , Abou-Rizk Samer , Kamar Amina , Nemer Georges , Bassim Marc
Published: January 2020

Background

Hearing loss (HL) represents the most common congenital sensory impairment with an incidence of 1–5 per 1000 live births. Non-syndromic hearing loss (NSHL) is an isolated finding that is not part of any other disorder accounting for 70% of all genetic hearing loss cases.

Methods

In the current study, we reported a polygenic mode of inheritance in an NSHL consanguineous family using exome sequencing technology and we evaluated the possible effect of the detected single nucleotide variants (SNVs) using in silico methods.

Results

Two bi-allelic SNVs were detected in the affected patients; a MYO15A (. p.V485A) variant, and a novel MITF (p.P338L) variant. Along with these homozygous mutations, we detected two heterozygous variants in well described hearing loss genes (MYO7A and MYH14). The novel MITF p. Pro338Leu missense mutation was predicted to change the protein structure and function.

Conclusion

A novel MITF mutation along with a previously described MYO15A mutation segregate with an autosomal recessive non-syndromic HL case with a post-lingual onset. The findings highlight the importance of carrying whole exome sequencing for a comprehensive assessment of HL genetic heterogeneity.
Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA): A developmental cohort study protocol
Authors:   The cVEDA Consortium, Sharma Eesha , Vaidya Nilakshi , Iyengar Udita , Zhang Yuning , Holla Bharath , Purushottam Meera , Chakrabarti Amit , Fernandes Gwen Sascha , Heron Jon , Hickman Matthew , Desrivieres Sylvane , Kartik Kamakshi , Jacob Preeti , Rangaswamy Madhavi , Bharath Rose Dawn , Barker Gareth , Orfanos Dimitri Papadopoulos , Ahuja Chirag , Murthy Pratima , Jain Sanjeev , Varghese Mathew , Jayarajan Deepak , Kumar Keshav , Thennarasu Kandavel , Basu Debashish , Subodh B. N. , Kuriyan Rebecca , Kurpad Sunita Simon , Kalyanram Kumaran , Krishnaveni Ghattu , Krishna Murali , Singh Rajkumar Lenin , Singh L. Roshan , Kalyanram Kartik , Toledano Mireille , Schumann Gunter , Benegal Vivek
Published: January 2020

Background

Low and middle-income countries like India with a large youth population experience a different environment from that of high-income countries. The Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA), based in India, aims to examine environmental influences on genomic variations, neurodevelopmental trajectories and vulnerability to psychopathology, with a focus on externalizing disorders.

Methods

cVEDA is a longitudinal cohort study, with planned missingness design for yearly follow-up. Participants have been recruited from multi-site tertiary care mental health settings, local communities, schools and colleges. 10,000 individuals between 6 and 23 years of age, of all genders, representing five geographically, ethnically, and socio-culturally distinct regions in India, and exposures to variations in early life adversity (psychosocial, nutritional, toxic exposures, slum-habitats, socio-political conflicts, urban/rural living, mental illness in the family) have been assessed using age-appropriate instruments to capture socio-demographic information, temperament, environmental exposures, parenting, psychiatric morbidity, and neuropsychological functioning. Blood/saliva and urine samples have been collected for genetic, epigenetic and toxicological (heavy metals, volatile organic compounds) studies. Structural (T1, T2, DTI) and functional (resting state fMRI) MRI brain scans have been performed on approximately 15% of the individuals. All data and biological samples are maintained in a databank and biobank, respectively.

Discussion

The cVEDA has established the largest neurodevelopmental database in India, comparable to global datasets, with detailed environmental characterization. This should permit identification of environmental and genetic vulnerabilities to psychopathology within a developmental framework. Neuroimaging and neuropsychological data from this study are already yielding insights on brain growth and maturation patterns.
Abnormal expression of rno_circRNA_014900 and rno_circRNA_005442 induced by ketamine in the rat hippocampus
Authors: Mao Jing , Li Tianmei , Fan Di , Zhou Hongli , Feng Jianguo , Liu Li , Zhang Chunxiang , Wang Xiaobin
Published: January 2020

Background

Recent studies have shown that circular RNA (circRNA) is rich in microRNA (miRNA) binding sites. We have previously demonstrated that the antidepressant effect of ketamine is related to the abnormal expression of various miRNAs in the brain. This study determined the expression profile of circRNAs in the hippocampus of rats treated with ketamine.

Methods

The aberrantly expressed circRNAs in rat hippocampus after ketamine injection were analyzed by microarray chip, and we further validated these circRNAs by quantitative reverse-transcription PCR (qRT-PCR). The target genes of the different circRNAs were predicted using bioinformatic analyses, and the functions and signal pathways of these target genes were investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.

Results

Microarray analysis showed that five circRNAs were aberrantly expressed in rat hippocampus after ketamine injection (fold change > 2.0, p < 0.05). The results from the qRT-PCR showed that one of the circRNAs was significantly increased (rno_circRNA_014900; fold change = 2.37; p = 0.03), while one was significantly reduced (rno_circRNA_005442; fold change = 0.37; p = 0.01). We discovered a significant enrichment in several GO terms and pathways associated with depression.

Conclusion

Our findings showed the abnormal expression of ketamine-induced hippocampal circRNAs in rats.
Bioscience learning in nursing: a cross-sectional survey of beginning nursing students in Norway
Authors: Evensen Aud Emelie , Brataas Hildfrid Vikkelsmoe , Cui Guanglin
Published: January 2020

Background

Taking bioscience courses such as anatomy and physiology (A&P) is important for the development of nursing competence, but learning such subjects is also a challenge for many students. Nursing students’ motivation, academic performance and exposure to different teaching methods may influence the learning process.

Methods

A descriptive survey was conducted with first-year nursing students at a university in Central Norway to explore their motivations, academic performance, and responses to various teaching methods used in an A&P course.

Results

The study provided insight into nursing students motivation, academic performance, and responses to various teaching approaches. 57 students participated in the survey and 91 % of them passed the course. The majority (61.4%) reported that classroom lecture was the most efficient and appreciated teaching method. Independent study was significantly associated with higher A&P exam grades (p-value < 0.05).

Conclusion

The survey suggests a need for further research about the quality, and presentation of anatomy and physiology units.
Development of therapeutic antibodies for the treatment of diseases
Authors: Lu Ruei-Min , Hwang Yu-Chyi , Liu I-Ju , Lee Chi-Chiu , Tsai Han-Zen , Li Hsin-Jung , Wu Han-Chung
Published: January 2020

It has been more than three decades since the first monoclonal antibody was approved by the United States Food and Drug Administration (US FDA) in 1986, and during this time, antibody engineering has dramatically evolved. Current antibody drugs have increasingly fewer adverse effects due to their high specificity. As a result, therapeutic antibodies have become the predominant class of new drugs developed in recent years. Over the past five years, antibodies have become the best-selling drugs in the pharmaceutical market, and in 2018, eight of the top ten bestselling drugs worldwide were biologics. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018 and is expected to generate revenue of $150 billion by the end of 2019 and $300 billion by 2025. Thus, the market for therapeutic antibody drugs has experienced explosive growth as new drugs have been approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases. As of December 2019, 79 therapeutic mAbs have been approved by the US FDA, but there is still significant growth potential. This review summarizes the latest market trends and outlines the preeminent antibody engineering technologies used in the development of therapeutic antibody drugs, such as humanization of monoclonal antibodies, phage display, the human antibody mouse, single B cell antibody technology, and affinity maturation. Finally, future applications and perspectives are also discussed.
An in vitro toolbox to accelerate anti-malarial drug discovery and development
Authors: Charman Susan A. , Andreu Alice , Barker Helena , Blundell Scott , Campbell Anna , Campbell Michael , Chen Gong , Chiu Francis C. K. , Crighton Elly , Katneni Kasiram , Morizzi Julia , Patil Rahul , Pham Thao , Ryan Eileen , Saunders Jessica , Shackleford David M. , White Karen L. , Almond Lisa , Dickins Maurice , Smith Dennis A. , Moehrle Joerg J. , Burrows Jeremy N. , Abla Nada
Published: January 2020

Background

Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles.

Methods

Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC–MS/MS.

Results

Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds.

Conclusions

This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug–drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
Correction to: Current outlook on radionuclide delivery systems: from design consideration to translation into clinics
Authors: Peltek Oleksii O. , Muslimov Albert R. , Zyuzin Mikhail V. , Timin Alexander S.
Published: January 2020

After publication of this article, an error was found in the description of the holmium isotopes. 165Ho is a stable isotope a fraction of which is activated to 166Ho by neutron activation in a nuclear reactor [2]. In one paragraph of the published article, describing holmium containing QuiremSpheres, 165Ho should be replaced with 166Ho. The correct description is given below.
Bi-directional prospective associations between objectively measured physical activity and fundamental motor skills in children: a two-year follow-up
Authors: Nilsen Ada Kristine Ofrim , Anderssen Sigmund Alfred , Johannessen Kjersti , Aadland Katrine Nyvoll , Ylvisaaker Einar , Loftesnes Jan Morten , Aadland Eivind
Published: January 2020

Background

The direction of the longitudinal relationship between physical activity (PA) and fundamental motor skills (FMS) remains unclear. We evaluated the bi-directional, prospective relationships between intensity-specific physical activity (PA) and domain-specific fundamental motor skills (FMS) over 2 years in children attending preschool at baseline.

Methods

A sample of 230 children (mean age at baseline 4.7 yr, 52% boys) from the 'Sogn og Fjordane Preschool Physical Activity Study' was measured 2 years apart. PA was assessed using ActiGraph accelerometers (GT3X+). FMS were evaluated by a test battery guided by the 'Test of Gross Motor Development 3' and the 'Preschooler Gross Motor Quality Scale'. PA outcomes were total PA (TPA [counts per minute]) and intensity specific PA and sedentary behaviour (SED) (min/day). FMS outcomes were locomotor, object control, and balance skills. Linear mixed model adjusting for potential co-variates was used to evaluate the bi-directional prospective associations between these variables, including the moderating effect of sex and age.

Results

Baseline total PA, moderate-to-vigorous PA (MVPA), and vigorous PA predicted higher locomotor, object control, and balance skills at follow-up (standardized regression coefficient (β): 0.17 to 0.26, p = 0.002–0.017). Baseline SED predicted lower locomotor skills at follow-up (β: − 0.27, p = 0.012). Baseline light PA did not predict FMS at follow-up. Baseline FMS were not associated with PA or SED at follow-up.

Conclusions

MVPA was positively associated with development of FMS in young children. In contrast, FMS were not related to future PA levels. Our results suggest promotion of MVPA is important for FMS development in young children.
Persistent osteoarticular pain in children: early clinical and laboratory findings suggestive of acute lymphoblastic leukemia (a multicenter case-control study of 147 patients)
Authors:   on behalf of the GOCE Group, Louvigné Mathilde , Rakotonjanahary Josué , Goumy Laurence , Tavenard Aude , Brasme Jean-François , Rialland Fanny , Baruchel André , Auclerc Marie-Françoise , Despert Véronique , Desgranges Marie , Jean Sylvie , Faye Albert , Meinzer Ulrich , Lorrot Mathie , Job-Deslandre Chantal , Bader-Meunier Brigitte , Gandemer Virginie , Pellier Isabelle
Published: January 2020

Background

The aim of this study was to identify early clinical and laboratory features that distinguish acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) in children presenting with persistent bone or joint pain for at least 1 month.

Methods

We performed a multicenter case-control study and reviewed medical records of children who initially presented with bone or joint pain lasting for at least 1 month, all of whom were given a secondary diagnosis of JIA or ALL, in four French University Hospitals. Each patient with ALL was paired by age with two children with JIA. Logistic regression was used to compare clinical and laboratory data from the two groups.

Results

Forty-nine children with ALL and 98 with JIA were included. The single most important feature distinguishing ALL from JIA was the presence of hepatomegaly, splenomegaly or lymphadenopathy; at least one of these manifestations was present in 37 cases with ALL, but only in 2 controls with JIA, for an odds ratio (OR) of 154 [95%CI: 30–793] (regression coefficient: 5.0). If the presence of these findings is missed or disregarded, multivariate analyses showed that non-articular bone pain and/or general symptoms (asthenia, anorexia or weight loss) (regression coefficient: 4.8, OR 124 [95%CI: 11.4–236]), neutrophils < 2 × 109/L (regression coefficient: 3.9, OR 50 [95%CI: 4.3–58]), and platelets < 300 × 109/L (regression coefficient: 2.6, OR 14 [95%CI: 2.3–83.9]) were associated with the presence of ALL (area under the ROC curve: 0.96 [95%CI: 0.93–0.99]).

Conclusions

Based on our findings we propose the following preliminary decision tree to be tested in prospective studies: in children presenting with at least 1 month of osteoarticular pain and no obvious ALL in peripheral smear, perform a bone marrow examination if hepatomegaly, splenomegaly or lymphadenopathy is present. If these manifestations are absent, perform a bone marrow examination if there is fever or elevated inflammatory markers associated with non-articular bone pain, general symptoms (asthenia, anorexia or weight loss), neutrophils < 2 × 109/L or platelets < 300 × 109/L.
Prognostic value of PD-L1 expression on tumor cells combined with CD8+ TIL density in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy
Authors: Gennen Kathrin , Käsmann Lukas , Taugner Julian , Eze Chukwuka , Karin Monika , Roengvoraphoj Olarn , Neumann Jens , Tufman Amanda , Orth Michael , Reu Simone , Belka Claus , Manapov Farkhad
Published: January 2020

Background/aim

mmune checkpoint inhibition (CPI) has an increasing impact in the multimodal treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Increasing evidence suggests treatment outcome depending on tumor cell PD-L1 expression. The purpose of this retrospective study was to investigate the prognostic value of PD-L1 expression on tumor cells in combination with CD8+ tumor stroma-infiltrating lymphocyte (TIL) density in inoperable LA-NSCLC treated with concurrent chemoradiotherapy (CRT).

Patients and method

We retrospectively assessed clinical characteristics and initial tumor biopsy samples of 31 inoperable LA-NSCLC patients treated with concurrent CRT. Prognostic impact of tumor cell PD-L1 expression (0% versus ≥1%) and CD8+ TIL density (0–40% vs. 41–100%) for local control, progression-free (PFS) and overall survival (OS) as well as correlations with clinicopathological features were evaluated.

Results

Median OS was 14 months (range: 3–167 months). The OS rates at 1- and 2 years were 68 and 20%. Local control of the entire cohort at 1 and 2 years were 74 and 61%. Median PFS, 1-year and 2-year PFS were 13 ± 1.4 months, 58 and 19%. PD-L1 expression < 1% on tumor cells was associated with improved OS, PFS and local control in patients treated with concurrent CRT. Univariate analysis showed a trend towards improved OS and local control in patients with low CD8+ TIL density. Evaluation of Tumor Immunity in the MicroEnvironment (TIME) appears to be an independent prognostic factor for local control, PFS and OS. The longest and shortest OS were achieved in patients with type I (PD-L1neg/CD8low) and type IV (PD-L1pos/CD8low) tumors (median OS: 57 ± 37 vs. 10 ± 5 months, p = 0.05), respectively.

Conclusion

Assessment of PD-L1 expression on tumor cells in combination with CD8+ TIL density can be a predictive biomarker in patients with inoperable LA-NSCLC treated with concurrent CRT.
IRS1/PI3K/AKT pathway signal involved in the regulation of glycolipid metabolic abnormalities by Mulberry (Morus alba L.) leaf extracts in 3T3-L1 adipocytes
Authors: Meng Qinghai , Qi Xu , Chao Ying , Chen Qi , Cheng Peng , Yu Xichao , Kuai Meiyu , Wu Jingzhen , Li Wenwen , Zhang Qichun , Li Yu , Bian Huimin
Published: January 2020

Background

Mulberry (Morus alba L.) leaf tea benefits the control of diabetes in Asian nations. This study was aim to investigate if the flavonoids, which extracts from mulberry leaves, could regulate the metabolism of glycolipid, and to investigate if flavonoids could regulate IRS1/PI3K/AKT pathway signal to affect the expression of FAS and membrane transfer capacity GLUT4 in 3T3-L1 adipocytes.

Results

Results revealed that flavonoids decreased the levels of free fatty acid and increased the glucose consumption and the levels of adiponectin and leptin in a dose-dependent manner, and remarkably increased the protein expression levels of p-IRS1, p-PI3K, p-Akt, total GLUT4, and membrane GLUT4, and decreased the protein expression levels of PTEN and FAS in 3T3-L1 adipocytes IR model. On the other hand, wortmannin (2 nM), a selective and irreversible PI3K inhibitor, significantly decreased the glucose consumption and the adiponectin and leptin levels, and increased the free fatty acid level in flavonoids treated 3T3-L1 adipocytes IR model. Furthermore, wortmannin (2 nM) partly eliminated the activation of PI3K/AKT signaling, the suppression of FAS, and the up-regulated membrane transfer capacity of GLUT4 in flavonoids treated 3T3-L1 adipocytes IR model.

Conclusion

In conclusion, our results illustrated that mulberry leaf extracts flavonoids alleviated the glycolipid metabolic abnormalities in 3T3-L1 adipocytes IR model, and the effect was associated with the activation of IRS1/PI3K/AKT pathway, the suppression of FAS, and the up-regulation of membrane transfer capacity of GLUT4.
Protocol for the Process Evaluation of the Online Remote Behavioural Intervention for Tics (ORBIT) randomized controlled trial for children and young people
Authors: Khan K. , Hollis C. , Hall C. L. , Davies E. B. , Mataix-Cols D. , Andrén P. , Murphy T. , Brown B. J. , Murray E. , Glazebrook C.
Published: January 2020

Background

Process evaluations are an important component in the interpretation and understanding of outcomes in trials. The Online Remote Behavioural Intervention for Tics (ORBIT) study is a randomized controlled trial evaluating the effectiveness of an Internet-delivered behavioural intervention (called BIP TIC) compared to an Internet-delivered education programme aimed at children and young people with tics. A process evaluation will be undertaken alongside the main trial to determine precisely how the behavioural intervention works and ascertain whether, and if so, how, the intervention could be successfully implemented in standard clinical practice. This protocol paper describes the rationale, aims, and methodology of the ORBIT trial process evaluation.

Methods

The process evaluation will have a mixed-methods design following the UK Medical Research Council 2015 guidelines, comprising both quantitative and qualitative data collection. This will include analysing data usage of participants in the intervention arm; purposively sampled, semi-structured interviews of parents and children, therapists and supervisors, and referring clinicians of the ORBIT trial, as well as analysis of qualitative comments put into the online therapy platform by participants at the end of treatment. Qualitative data will be analysed thematically. Quantitative and qualitative data will be integrated in a triangulation approach, to provide an understanding of how the intervention works, and what resources are needed for effective implementation, uptake and use in routine clinical care.

Discussion

This process evaluation will explore the experiences of participants, therapists and supervisors and referring clinicians of a complex online intervention. By contextualising trial efficacy results, this will help understand how and if the intervention worked and what may be required to sustain the implementation of the treatment long term. The findings will also aid in our understanding of factors that can affect the success of complex interventions. This will enable future researchers developing online behavioural interventions for children and young people with mental health and neurological disorders to gain invaluable information from this process evaluation.

Trial registration

International Standard Randomised Controlled Trials Number, ISRCTN70758207. Registered on 20 March 2018.

ClinicalTrials.gov, NCT03483493. Registered on 30 March 2018.
Treatment of non-high-risk acute promyelocytic leukemia with realgar-indigo naturalis formula (RIF) and all-trans retinoid acid (ATRA): study protocol for a randomized controlled trial
Authors: Zhang Xinxin , Liu Li , Yao Yazhou , Gong Sha , Wang Mengchang , Xi Jieying , Chen Limei , Wei Suhua , Zhang Huiyun , Zhao Chenyang , Wang Huaiyu
Published: January 2020

Background

Acute promyelocytic leukemia (APL) is a highly curable disease when treated with all-trans retinoid acid (ATRA) and arsenic trioxide (ATO). The combination of ATO and ATRA has become the standard therapeutic protocol for induction therapy in non-high-risk APL. An oral arsenic realgar-indigo naturalis formula (RIF) has also showed high efficacy and it has a more convenient route of administration than the standard intravenous regimen. Unlike in previous trials, the arsenical agent was used simultaneously with ATRA during post-remission therapy in this trial.

Methods

This study was designed as a multicenter, randomized controlled trial. The trial has a non-inferiority design with superiority being explored if non-inferiority is identified. All patients receive ATRA-ATO during the induction therapy. After achieving hematologic complete remission (HCR), patients were randomly assigned (1:1) to receive treatment with ATRA-RIF (experimental group) or ATRA-ATO (control group) as the consolidation therapy. During the consolidation therapy, the two groups receive ATRA plus RIF or intravenous ATO 2 weeks on and 2 to ~ 4 weeks off until molecular complete remission (MCR), then ATRA and oral RIF 2 weeks on and 2 to ~ 4 weeks off giving a total of six courses.

Discussion

This trial aims to compare the efficacy of ATRA-ATO versus ATRA-RIF in non-high-risk patients with APL, to demonstrate that oral RIF application reduces the total hospitalization days and medical costs. The simple schedule was studied in this trial.

Trial registration

ClinicalTrials.gov, NCT02899169. Registered on 14 September 2016.
Associations between intestinal parasitic infections, anaemia, and diarrhoea among school aged children, and the impact of hand-washing and nail clipping
Authors: Mahmud Mahmud Abdulkader , Spigt Mark , Bezabih Afework Mulugeta , Dinant Geert-Jan , Velasco Roman Blanco
Published: January 2020

Objective

In marginalized setting, under-nutrition and illnesses due to infectious agents create a vicious circle. In our previous study, we reported that easy-to-do hand hygiene interventions were effective in preventing intestinal parasite infections (IPIs) and reduce the rate of anaemia among school-aged children. The aim of this study was to assess the pattern of associations between IPIs, anaemia and diarrhoea among the school-aged children and to explore if the observed impact of hand-washing and nail clipping interventions in our findings was similar across children with different baseline demographic and disease characteristics. The study was based on the analysis of data that was collected during the randomized controlled trial and hence have used the same study participants and study area.

Results

Children with IPIs had a much higher chance of also being anaemic (AOR 2.09, 95% CI 1.15–3.80), having diarrhoea (AOR 2.83, 95% CI 1.57–5.09), and vice versa. Anaemia and diarrhoea were very strongly related (AOR 9.62, 95% CI 5.18–17.85). Overall, hand-washing with soap at key times and weekly nail clipping were efficacious in preventing intestinal parasite re-infection among children despite the differences in baseline demographic characteristics.

Trial registration: NCT01619254 (June 09/2012)
Anticholinergics and benzodiazepines on cognitive impairment among elderly with Alzheimer’s disease: a 1 year follow-up study
Authors: Jenraumjit Rewadee , Chinwong Surarong , Chinwong Dujrudee , Kanjanarach Tipaporn , Kshetradat Thanat , Wongpakaran Tinakon , Wongpakaran Nahathai
Published: January 2020

Objective

Age-associated decline in central cholinergic activity makes older adults susceptible to harmful effects of anticholinergics (ACs). Evidence exists of an association between effects of AC medications on cognition. This retrospective cohort study examines how ACs affect cognition among older adults with Alzheimer’s disease (AD) who received acetylcholine esterase inhibitors (AChEIs) over the course of 12 months.

Results

A total of 133 (80% women, mean age 78.38 years, SD 7.4) were recruited. No difference in sex, age and comorbid diseases was observed between participants who took ACs, benzodiazepines (BZDs) and AChEIs. The most common prescribed ACs was quetiapine, being used for behavioral and psychological symptoms (BPSD). Multilevel analysis showed that the change of mental state examination scores were significantly predicted in the group using ACs (t (169), − 2.52, p = .020) but not with the groups using BZD (t (162), 0.84, p = .440). Evidence showed that older adults with Alzheimer’s disease and exposed to ACs exhibited lower global cognitive scores than those without AC exposure. Using ACs could be a trade-off between controlling BPSD and aggravating cognitive impairment. Highlighting the awareness of the potential anticholinergic effect is important and may be the best policy.
Low plasma neurofilament light levels associated with raised cortical microglial activation suggest inflammation acts to protect prodromal Alzheimer’s disease
Authors: Parbo Peter , Madsen Lasse Stensvig , Ismail Rola , Zetterberg Henrik , Blennow Kaj , Eskildsen Simon F. , Vorup-Jensen Thomas , Brooks David J.
Published: January 2020

Background

Plasma and cerebrospinal fluid levels of neurofilament light (NfL), a marker of axonal degeneration, have previously been reported to be raised in patients with clinically diagnosed Alzheimer’s disease (AD). Activated microglia, an intrinsic inflammatory response to brain lesions, are also known to be present in a majority of Alzheimer or mild cognitive impaired (MCI) subjects with raised β-amyloid load on their positron emission tomography (PET) imaging. It is now considered that the earliest phase of inflammation may be protective to the brain, removing amyloid plaques and remodelling synapses. Our aim was to determine whether the cortical inflammation/microglial activation load, measured with the translocator protein marker 11C-PK11195 PET, was correlated with plasma NfL levels in prodromal and early Alzheimer subjects.

Methods

Twenty-seven MCI or early AD cases with raised cortical β-amyloid load had 11C-(R)-PK11195 PET, structural and diffusion magnetic resonance imaging, and levels of their plasma NfL measured. Correlation analyses were performed using surface-based cortical statistics.

Results

Statistical maps localised areas in MCI cases where levels of brain inflammation correlated inversely with plasma NfL levels. These areas were localised in the frontal, parietal, precuneus, occipital, and sensorimotor cortices. Brain inflammation correlated negatively with mean diffusivity (MD) of water with regions overlapping.

Conclusion

We conclude that an inverse correlation between levels of inflammation in cortical areas and plasma NfL levels indicates that microglial activation may initially be protective to axons in AD. This is supported by the finding of an inverse association between cortical water diffusivity and microglial activation in the same regions. Our findings suggest a rationale for stimulating microglial activity in early and prodromal Alzheimer cases—possibly using immunotherapy. Plasma NfL levels could be used as a measure of the protective efficacy of immune stimulation and for monitoring efficacy of putative neuroprotective agents.
European intensive care physicians’ experience of infections due to antibiotic-resistant bacteria
Authors: Lepape Alain , Jean Astrid , De Waele Jan , Friggeri Arnaud , Savey Anne , Vanhems Philippe , Gustin Marie Paule , Monnet Dominique L. , Garnacho-Montero José , Kohlenberg Anke
Published: January 2020

Background

Antimicrobial resistance (AMR) compromises the treatment of patients with serious infections in intensive care units (ICUs), and intensive care physicians are increasingly facing patients with bacterial infections with limited or no adequate therapeutic options. A survey was conducted to assess the intensive care physicians’ perception of the AMR situation in the European Union/European Economic Area (EU/EEA).

Methods

Between May and July 2017, physicians working in European ICUs were invited to complete an online questionnaire hosted by the European Society of Intensive Care Medicine. The survey included 20 questions on hospital and ICU characteristics, frequency of infections with multidrug-resistant (MDR) bacteria and relevance of AMR in the respondent’s ICU, management of antimicrobial treatment as well as the use of last-line antibiotics in the six months preceding the survey. For the analysis of regional differences, EU/EEA countries were grouped into the four sub-regions of Eastern, Northern, Southern and Western Europe.

Results

Overall, 1062 responses from four European sub-regions were analysed. Infections with MDR bacteria in their ICU were rated as a major problem by 257 (24.2%), moderate problem by 360 (33.9%) and minor problem by 391 (36.8%) respondents. Third-generation cephalosporin-resistant Enterobacteriaceae were the most frequently encountered MDR bacteria followed by, in order of decreasing frequency, meticillin-resistant Staphylococcus aureus, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Pseudomonas aeruginosa and vancomycin-resistant enterococci. Perception of the relevance of the AMR problem and the frequency of specific MDR bacteria varied by European sub-region. Bacteria resistant to all or almost all available antibiotics were encountered by 132 (12.4%) respondents. Many physicians reported not having access to specific last-line antibiotics.

Conclusions

The percentage of European ICU physicians perceiving AMR as a substantial problem in their ICU is high with variation by sub-region in line with epidemiological studies. The reports of bacteria resistant to almost all available antibiotics and the limited availability of last-line antibiotics in ICUs in the EU/EEA are of concern.