bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimalarial activity of traditional Kampo medicine Coptis Rhizome extract and its major active compounds
Authors: Teklemichael Awet Alem , Mizukami Shusaku , Toume Kazufumi , Mosaddeque Farhana , Kamel Mohamed Gomaa , Kaneko Osamu , Komatsu Katsuko , Karbwang Juntra , Huy Nguyen Tien , Hirayama Kenji 
Published: June 2020

Abstract
Background: The herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, examined a variety of Japanese traditional herbal medicine (Kampo) for their potential antimalarial activities. Methods: We designed a comprehensive screening to identify novel antimalarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n=96). The antimalarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and -resistant (Dd2) strains of Plasmodium falciparum . The cytotoxicity was also evaluated using primary Adult Mouse Brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo antimalarial activity. Results: Out of 120 herbal extracts, Coptis Rhizome showed the highest antimalarial activity (IC 50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis Rhizome also showed antimalarial activities with IC 50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest antimalarial activity (IC 50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. . Finally, the herbal extract of Coptis Rhizome and its major active compound coptisine chloride exhibited significant antimalarial activity in mice infected with P. yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P <.05) for Coptis Rhizome and from 81 to 89% (P <.01) for coptisine chloride. Conclusion: Coptis Rhizome and its major active compound coptisine chloride showed promising antimalarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus Kampo herbal medicine is a potential natural resource for novel antipathogenic agents.
Multivariate Network Meta-Analysis Incorporating Class Effects
Authors: Owen Rhiannon Kate , Bujkiewicz Sylwia , Tincello Douglas G , Abrams Keith R 
Published: June 2020

Abstract
Background: Network meta-analysis synthesises data from a number of clinical trials in order to assess the comparative efficacy of multiple healthcare interventions in similar patient populations. In situations where clinical trial data are heterogeneously reported i.e. data are missing for one or more outcomes of interest, synthesising such data can lead to disconnected networks of evidence, increased uncertainty, and potentially biased estimates which can have severe implications for decision-making. To overcome this issue, strength can be borrowed between outcomes of interest in multivariate network meta-analyses. Furthermore, in situations where there are relatively few trials informing each treatment comparison, there is a potential issue with the sparsity of data in the treatment networks, which can lead to substantial parameter uncertainty. A multivariate network meta-analysis approach can be further extended to borrow strength between interventions of the same class using hierarchical models. Methods: We extend the trivariate network meta-analysis model to incorporate the exchangeability between treatment effects belonging to the same class of intervention to increase precision in treatment effect estimates. We further incorporate a missing data framework to estimate uncertainty in trials that fail to report measures of variability in order to maximise the use of all available information for healthcare decision-making. The methods are applied to a motivating dataset in overactive bladder syndrome. The outcomes of interest were mean change from baseline in incontinence, voiding and urgency episodes. All models were tted using Bayesian Markov Chain Monte Carlo (MCMC) methods in WinBUGS. Results: All models (univariate, multivariate, and multivariate models incorporating class effects) produced similar point estimates for all treatment effects. Incorporating class effects in multivariate models often increased precision in treatment effect estimates. Conclusions: Multivariate network meta-analysis incorporating class effects allowed for the comparison of all interventions across all outcome measures to ameliorate the potential impact of outcome reporting bias, and further borrowed strength between interventions belonging to the same class of treatment to increase the precision in treatment effect estimates for healthcare policy and decision-making. Keywords: multivariate; network meta-analysis; mixed treatment comparisons; meta-analysis; class effect
Comparison of hierarchical EMAX and NDLM models in dose-response for early phase clinical trials
Authors: Huang Xiaqing , Gajewski Byron 
Published: June 2020

Abstract
Background: Phase II clinical trials primarily aim to find the optimal dose and investigate the relationship between dose and efficacy relative to standard of care (control). Therefore, before moving forward to a phase III confirmatory trial, the most effective dose is needed to be identified. Methods: The primary endpoint of a phase II trial is typically a binary endpoint of success or failure. The EMAX model, ubiquitous in pharmacology research, was fit for many compounds and described the data well, except for a single compound, which had nonmonotone dose–response (Thomas et al., 2014). To mitigate the risk of nonmonotone dose response one of the alternative options is a Bayesian hierarchical EMAX model (Gajewski et al., 2019). The hierarchical EMAX adapts to its environment. Results: When the dose-response curve is monotonic it enjoys the efficiency of EMAX. When the dose-response curve is non-monotonic the additional random effect hyperprior makes the hierarchical EMAX model more adjustable and flexible. However, the normal dynamic linear model (NDLM) is a useful model to explore dose-response relationships in that the efficacy at the current dose depends on the efficacy of the previous dose(s). Previous research has compared the EMAX to the hierarchical EMAX (Gajewski et al., 2019) and the EMAX to the NDLM (Liu et al., 2017), however, the hierarchical EMAX has not been directly compared to the NDLM. Conclusions: The focus of this paper is to compare these models and discuss the relative merit for each of their uses for an ongoing early phase dose selection study.
14-type HPV mRNA test in triage of HPV DNA positive postmenopausal women with normal cytology
Authors: Asciutto Katrin Christine , Borgfeldt Christer , Forslund Ola 
Published: June 2020

Abstract
Background: During 2013 and 2016 the Region of Skåne, Sweden, started to analyse human papillomavirus (HPV) and cytology in postmenopausal women 60-65 years of age. Our aim was to evaluate high-risk (HR) HPV mRNA testing for the triage of HPV DNA positive postmenopausal women with normal cytology. Methods: A total of 271 women, 60-65 years of age, underwent liquid based cytology (LBC) and HPV testing by using the HR-HPV DNA MGP-PCR-Luminex assay. HR-HPV DNA-positive women with normal cytology underwent complimentary HPV mRNA testing (Aptima, Hologic Inc.). Over a period of 49 months (SD 11.0) the women received regular follow-up at intervals of 12-18 months. Women with abnormal cytology and/or a positive HR-HPV DNA and/or mRNA result at two subsequent visits were scheduled for colposcopy and clinical examination. Results: Over the surveillance period, 3.6% (10/271) of the HR-HPV DNA positive women developed histologically confirmed high-grade squamous intraepithelial lesions (HSILs) or worse. The cumulative incidence rates (CIR) were 29.7% (CI 24.8-30.1) for HSIL or worse among HPV mRNA-positive women at enrolment (39.5% 107/271) and 0% among HPV mRNA negative women (60.5%, 164/271), (p=0.002). Conclusions : Postmenopausal women with normal cytology along with the presence of HR-HPV mRNA are at increased risk for development of severe cervical dysplasia, in contrast to those women with negative HR-HPV mRNA. The HR-HPV mRNA APTIMA assay detecting 14 HR-HPV types may be a useful triage method among HPV DNA positive postmenopausal women with normal cytology.
Hepatocyte growth factor (HGF) and stem cell factor (SCF) maintained the stemness of human bone marrow mesenchymal stem cells (hBMSCs) during long-term expansion by preserving mitochondrial function via the PI3K/AKT, ERK1/2, and STAT3 signaling pathways
Authors: Cao Zeyuan , Xie Yunyi , Yu Le , Li Yi , Wang Yan 
Published: June 2020

Abstract
Background: Mesenchymal stem cells (MSCs) have a limited self-renewal ability, impaired multi-differentiation potential, and undetermined cell senescence during in vitro series expansion. To address this concern, we investigated the effects of the microenvironment provided by stem cells from human exfoliated deciduous teeth (SHED) in maintaining the stemness of human bone marrow mesenchymal stem cells (hBMSCs) and identified the key factors and possible mechanisms responsible for maintaining the stemness of MSCs during long-term expansion in vitro.Methods: The passage 3 (P3) to passage 8 (P8) hBMSCs were cultured in the conditioned medium from SHED (SHED-CM). The percentage of senescent cells was evaluated by β-galactosidase staining. In addition, the osteogenic differentiation potential was analyzed by reverse transcription quantitative PCR (RT-qPCR), Western blot, alizarin red and alkaline phosphatase (ALP) staining. Furthermore, RT-qPCR results identified hepatocyte growth factor (HGF) and stem cell factor (SCF) as key factors. Thus, the effects of HGF and SCF on mitochondrial function were assessed by measuring the ROS and mitochondrial membrane potential levels. Finally, selected mitochondrial-related proteins associated with the PI3K/AKT, ERK1/2, and STAT3 signaling pathways were investigated to determine the effects of HGF and SCF in preserving the mitochondrial function of hBMSCs during long-term expansion. Results: SHED-CM had significantly enhanced the cell proliferation, reduced the senescent cells, and maintained the osteogenesis and pro-angiogenic capacity in P8 hBMSCs during long-term expansion. In addition, hBMSCs treated with 100 ng/ml HGF and 10 ng/ml SCF had reduced ROS levels, and preserved mitochondrial membrane potential compared with P8 hBMSCs during long-term expansion. Furthermore, HGF and SCF upregulated the expression of mitochondrial-related proteins associated with the PI3K/AKT, ERK1/2, and STAT3 signaling pathways, possibly contributing to the maintenance of hBMSCs stemness by preserving mitochondrial function. Conclusion: Both HGF and SCF are key factors in maintaining the stemness of hBMSCs by preserving mitochondrial function through the expression of proteins associated with the PI3K/AKT, ERK1/2, and STAT3 signaling pathways. This study provides new insights into the anti-senescence capability of HGF and SCF, as well as new evidence for their potential application in optimizing the long-term culture of MSCs.
Translational Outcomes Relevant to Neurodevelopmental Disorders Following Early Life Exposure of Rats to Chlorpyrifos
Authors: Berg Elizabeth L , Ching Tianna M , Bruun Donald A , Rivera Josef K , Careaga Milo , Ellegood Jacob , Lerch Jason P , Wöhr Markus , Lein Pamela J , Silverman Jill 
Published: June 2020

Abstract
Background: Neurodevelopmental disorders (NDDs), including intellectual disability, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are pervasive, lifelong disorders for which pharmacological interventions are not readily available. Substantial increases in the prevalence of NDDs over a relatively short period cannot be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with exposure(s) to environmental risk factors during critical periods of neurodevelopment influence NDD susceptibility and symptom severity. Organophosphorus (OP) pesticides have been identified as potential environmental risk factors. Epidemiological studies suggest children exposed prenatally to the OP pesticide chlorpyrifos (CPF) have significant mental and motor delays and strong positive associations for the development of a clinical diagnosis of developmental delay, ADHD, or ASD. Methods: We tested the hypothesis that developmental CPF exposure impairs behavior relevant to NDD phenotypes, i.e., deficits in social communication and repetitive, restricted behavior. Male and female rat pups were exposed to CPF at 0.1, 1.0, or 3.0 mg/kg (s.c.) from postnatal days 1-4. Results: These CPF doses did not significantly inhibit acetylcholinesterase activity in the blood or brain but significantly impaired pup ultrasonic vocalizations (USV) in both sexes. Social communication in juveniles via positive affiliative 50-kHz USV playback was absent in females exposed to CPF at 0.3 mg/kg and 1.0 mg/kg. In contrast, this CPF exposure paradigm had no significant effect on gross locomotor abilities or contextual and cued fear memory. Ex vivo magnetic resonance imaging largely found no differences between the CPF rats and the corresponding vehicle controls; however there were some interesting trends in females at a dosage of 0.3 mg/kg. Conclusions: This work characterizes a rat model of developmental CPF exposure that exhibits adverse behavioral phenotypes resulting from perinatal exposures at levels that did not significantly inhibit acetylcholinesterase activity in brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered.
Community-Based Cluster Randomized Controlled Trial: Empowering Households to Identify and Provide Appropriate Care for Low-Birthweight Newborns in Nepal
Authors: Hodgins Stephen , Rajbhandari Binamra , Joshi Deepak , Ban Bharat , Khatry Subarna , Mullany Luke C 
Published: June 2020

Abstract
Background: Most newborn deaths occur among those of low birthweight (LBWt), due to prematurity &/or impaired fetal growth. Simple practices can substantially mitigate this risk. In low-income country settings where many births occur at home, strategies are needed that empower mothers to determine if their babies are higher risk and take measures to reduce risk. Earlier studies suggest that foot-length may be a good proxy for birthweight. An earlier Nepal study found a 6.9cm cut-off performed relatively well, differentiating normal from low birthweight.Methods: Community-based, cluster-randomized controlled trial. Objective: to determine whether family-administered screening, associated with targeted messages improves care practices known to mitigate LBWt-associated risks. Participants: women participating in a parent trial in rural Nepal, recruited late in pregnancy. Women were given a 6.9cm card to assess whether the baby’s foot is small; if so, to call a number on the card for advice. Follow-up visits were made over the 2 weeks following the birth, assessing for 2 behavioral outcomes: reported skin-to-skin thermal care, and care-seeking outside the home; assessed restricting to low birthweight (using 2 cutoffs: 2,500g and 2,000g). Randomization: 17 clusters intervention, 17 control.The study also documented performance along the presumed causal chain from intervention through behavioral impact.Results: 2,022 intervention, 2,432 control. Intervention arm: 519 had birthweight <2,500g (vs. 663 among controls), of which 503 were available for analysis (vs. 649 among controls). No significant difference found on care-seeking; for those <2,500g RR 1.13 (95%CI: 0.97-1.131). A higher proportion of those in the intervention arm reported skin-to-skin thermal care than among controls; for those <2,500g RR 2.50 (95%CI: 2.01-3.1). However, process measures suggest this apparent effect cannot be attributed to the intervention; the card performed poorly as a proxy for LBWt, misclassifying 84.5% of those <2,000 as normal.Conclusions: Although the trial found an apparent effect on one of the behavioral outcomes, this cannot be attributed to the intervention; most likely it was a result of pure chance. Other approaches are needed for identifying small, at-risk babies in such settings, and targeting them for appropriate care messaging.Trial registration: https://clinicaltrials.gov/ct2/show/NCT02802332, registered 6/16/2016.
The geno-spatio analysis of Mycobacterium tuberculosis complex in hot and cold spots of Guangxi, China
Authors: Lin Dingwen , Cui Zhezhe , Virasakdi Virasakdi , Palittapongarnpim Prasit , Chaiprasert Angkana , Ruangchai Wuthiwat , Ou Jing , Huang Liwen 
Published: June 2020

Abstract
Background At present, there are few studies on polymorphism of Mycobacterium tuberculosis (Mtb) gene and how it affects the TB epidemic. This study aimed to document the differences of polymorphisms between tuberculosis hot and cold spot areas of Guangxi Zhuang Autonomous Region, China. Methods The cold and hot spot areas, each with 3 counties, had been pre-identified by TB incidence for 5 years from the surveillance database. Whole genome sequencing analysis was performed on all sputum Mtb isolates from the detected cases during January and June 2018. Single nucleotide polymorphism (SNP) of each isolate compared to the H37Rv strain were called and used for lineage and sub-lineage identification. Pairwise SNP differences between every pair of isolates were computed. Analyses of Molecular Variance (AMOVA) across counties of the same hot or cold spot area and between the two areas were performed. Results As a whole, 59.8% (57.7% sub-lineage 2.2 and 2.1% sub-lineage 2.1) and 39.8% (17.8% sub-lineage 4.4, 6.5% sub-lineage 4.2 and 15.5% sub-lineage 4.5) of the Mtb strains were Lineage 2 and Lineage 4 respectively. The percentages of sub-lineage 2.2 (Beijing family strains) are significantly higher in hot spots. Through the MDS dimension reduction, the genomic population structure in the three hot spot counties is significantly different from those three cold spot counties (T-test p = 0.05). The median of SNPs distances among Mtb isolates in cold spots was greater than that in hot spots (897 vs 746, Rank-sum test p < 0.001). Three genomic clusters, each with genomic distance ≤ 12 SNPs, were identified with 2, 3 and 4 consanguineous strains. Two clusters were from hot spots and one was from cold spots. Conclusion Narrower genotype diversity in the hot area may indicate higher transmissibility of the Mtb strains in the area compared to those in the cold spot area.
Molecular detection of hemotropic mycoplasmas (hemoplasmas) in domestic cats (Felis catus) in Romania
Authors: Imre Mirela , Văduva Cristina , Dărăbuș Gheorghe , Morariu Sorin , Herman Viorel , Plutzer Judit , Suici Tijana , Lait Philippa , Imre Kálmán 
Published: June 2020

Abstract
Background: The hemotropic mycoplasmas (hemoplasmas) of the genus Mycoplasma are recognized as important bacteria that parasitize red blood cells, causing hemolytic anemia in many mammalian species, including cats. No information is available concerning the presence of feline hemoplasma infections in cats in Romania. Thus, the objective of the present study was to provide data on the occurrence and molecular characterization of hemotropic mycoplasmas in client-owned cats in Romania.Methods: Blood samples from 51 unhealthy cats, originating from Timişoara Municipality, Romania, were screened for the presence of hemoplasmas using conventional polymerase chain reaction targeting the 16S rRNA gene and sequencing assays. PCR-positive samples were subsequently analyzed by phylogenetic and population genetic analysis.Results: Molecular analysis revealed 11 (21.6%) positive samples, consisting of 8 (72.7%) Candidatus Mycoplasma haemominutum and 3 (27.3%) Mycoplasma haemofelis confirmed positives. Candidatus Mycoplasma turicensis was not detected, and no co-infections were registered. No significant associations (p > 0.05) were found between the hemoplasma infection status and age, gender, breed, presence of ectoparasites, feline leukemia virus/feline immunodeficiency virus (FeLV/FIV) positivity of cats, or the sampling season. However, outdoor access was positively associated (p=0.049) with infection and could be considered a risk factor (OR=4.1) in acquiring feline hemotropic mycoplasmas. Phylogenetic analysis revealed that our sequences clustered with those selected from the GenBank database in two distinct clades. The registered population genetic indices were strongly supportive of the great variance in sequences between the recorded Mycoplasma species.Conclusions: The findings support the occurrence of feline hemoplasma infections in previously uninvestigated territories of Europe, providing useful information for small animal practitioners. To our knowledge, the present survey is the first reported molecular evidence of feline hemoplasma infections in Romania.
Frequency of kdr mutations in the voltage-sensitive sodium channel (VSSC) gene in Aedes aegypti from Yogyakarta and implications for Wolbachia-infected mosquito trials
Authors: Wuliandari Juli R. , Hoffmann Ary A. , Tantowijoyo Warsito , Endersby-Harshman Nancy M. 
Published: June 2020

Abstract
Background: In the inner city of Yogyakarta, Indonesia, insecticide resistance is expected in the main dengue vector, Aedes aegypti, because of the intensive local application of pyrethroid insecticides. However, detailed information about the nature of resistance in this species is required to assist the release of Wolbachia mosquitoes in a dengue control program so that we can ensure that insecticide resistance in the strain of A. aegypti being released matches that of the background population.Methods: High-resolution melt genotyping was used to screen for kdr mutations associated with pyrethroid resistance in the voltage-sensitive sodium channel (VSSC) gene in A. aegypti of some areas in the inner city of Yogyakarta.Results: The results show that the V1016G mutation predominated, with individuals homozygous for the 1016G allele at a frequency of 82.1% and the mutant allele G at a frequency of 92%. Two patterns of co-occurrence of mutations were detected in this study, homozygous individuals V1016G/S989P; and heterozygous individuals V1016G/F1534C/S989P. We found the simultaneous occurrence of kdr mutations V1016G and F1534C at all collection sites, but not within individual mosquitoes. Homozygous mutants at locus 1016 were homozygous wildtype at locus 1534 and vice versa, and heterozygous V1016G were also heterozygous for F1534C. The most common tri-locus genotype co-occurrences were homozygous mutant 1016GG and homozygous wild-type FF1534, combined with homozygous mutant 989PP (GG/FF/PP) at a frequency of 38.28%.Conclusions: Given the relatively small differences in frequency of resistance alleles across the city area, locality variations in resistance should have minor implications for the success of Wolbachia mosquito trials being undertaken in the Yogyakarta area.