bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundModelling 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.MethodsIonization 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.ResultsBoth 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.ConclusionsThis 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.
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.