bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects
Authors: Bian Yicong , Zhang Hua , Ma Sheng , Jiao Yongyi , Yan Pangke , Liu Xiao , Ma Shiping , Xiong Yating , Gu Zheming , Yu Zhenwen , Huang Chenrong , Miao Liyan 
Published: May 2020

AimsThis trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects.MethodsA single dose of 0.4 mg/kg [14C]HSK3486 was administered to six healthy subjects. Blood, urine and faecal samples were collected, analysed for radioactivity, unchanged HSK3486 and profiled for metabolites. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and vital signs were closely monitored during the study.ResultsThe mean recovery of total radioactivity in excreta was 87.3% in 240 h, including 84.6% in urine and 2.65% in faeces. The exposure (AUC0‐t) of total radioactivity was much higher than that of unchanged HSK3486 in plasma, indicating there were circulating metabolites in plasma. The glucuronide conjugate of HSK3486 (M4) was found as the only major circulating metabolite in plasma (79.3%), while unchanged HSK3486 accounted for only 3.97% of the total radiation exposure. M4 also resulted in a longer estimated elimination half‐life (t1/2) of total radioactivity than that of unchanged HSK3486 in plasma. Fortunately, the metabolite was detected to be not specific to red blood cells and was suggested to be nonhypnotic and nontoxic. All the subjects were quickly anaesthetized (2 min) after drug administration and woke up smoothly after a short time (5.5–14.1 min) with few residual effects. The only adverse event in the study was mild (grade 1) and consisted of hypotension.ConclusionHSK3486 is a promising anaesthetic candidate with rapid onset of action and clear absorption, distribution, metabolism, excretion (ADME) processes. HSK3486 showed favourable pharmacokinetic characteristics, pharmacodynamic responses and safety at the study dose.
Evaluation of pharmacokinetic‐pharmacodynamic relationships and selection of drug combinations for tuberculosis
Authors: Muliaditan Morris , Della Pasqua Oscar 
Published: May 2020

AimsDespite evidence of the efficacy of anti‐tubercular drug regimens in clinical practice, the rationale underpinning the selection of doses and companion drugs for combination therapy remains empirical. Novel methods are needed to optimise the antibacterial activity in combination therapies. A drug–disease modelling framework for rational selection of dose and drug combinations in tuberculosis is presented here.MethodsA model‐based meta‐analysis was performed to assess the antibacterial activity of different combinations in infected mice. Data retrieved from the published literature were analysed using a two‐state bacterial growth dynamics model, including fast‐ and slow‐growing bacterial populations. The contribution of each drug to the overall antibacterial activity of the combination was parameterised as relative change to the potency of the backbone drug (EC50‐F and/or EC50‐S). Rifampicin and bedaquiline were selected as paradigm drugs to evaluate the predictive performance of the modelling approach.ResultsPyrazinamide increased the potency (EC50‐F and EC50‐S) of rifampicin (RZ) and bedaquiline (BZ) by almost two‐fold. By contrast, pretomanid and isoniazid were found to worsen the antibacterial activity of BZ and RZ, respectively. Following extrapolation of in vivo pharmacokinetic‐pharmacodynamic relationships, the dose of rifampicin showing maximum bactericidal effect in tuberculosis patients was predicted to be 70 mg·kg−1 when given in combination with pyrazinamide.ConclusionsThe use of a drug–disease modelling framework may provide a more robust rationale for extrapolation and selection of dose and companion drugs in humans. Our analysis demonstrates that RZ and BZ should be considered as a backbone therapy in prospective novel combination regimens against tuberculosis.
Robust and efficient semi‐supervised estimation of average treatment effects with application to electronic health records data
Authors: Cheng David , Ananthakrishnan Ashwin N. , Cai Tianxi 
Published: May 2020

AbstractWe consider the problem of estimating the average treatment effect (ATE) in a semi‐supervised learning setting, where a very small proportion of the entire set of observations are labeled with the true outcome but features predictive of the outcome are available among all observations. This problem arises, for example, when estimating treatment effects in electronic health records (EHR) data because gold‐standard outcomes are often not directly observable from the records but are observed for a limited number of patients through small‐scale manual chart review. We develop an imputation‐based approach for estimating the ATE that is robust to misspecification of the imputation model. This effectively allows information from the predictive features to be safely leveraged to improve efficiency in estimating the ATE. The estimator is additionally doubly‐robust in that it is consistent under correct specification of either an initial propensity score model or a baseline outcome model. It is also locally semiparametric efficient under an ideal semi‐supervised model where the distribution of the unlabeled data is known. Simulations exhibit the efficiency and robustness of the proposed method compared to existing approaches in finite samples. We illustrate the method by comparing rates of treatment response to two biologic agents for treatment inflammatory bowel disease using EHR data from Partners' Healthcare.
The Motivational Thought Frequency Scales for increased physical activity and reduced high‐energy snacking
Authors: Kavanagh David J. , Teixeira Hugo , Connolly Jennifer , Andrade Jackie , May Jon , Godfrey Shaneen , Carroll Amanda , Taylor Kimberly , Connor Jason P. 
Published: May 2020

ObjectivesThe Motivational Thought Frequency (MTF) Scale has previously demonstrated a coherent four‐factor internal structure (Intensity, Incentives Imagery, Self‐Efficacy Imagery, Availability) in control of alcohol and effective self‐management of diabetes. The current research tested the factorial structure and concurrent associations of versions of the MTF for increasing physical activity (MTF‐PA) and reducing high‐energy snacks (MTF‐S).DesignStudy 1 examined the internal structure of the MTF‐PA and its concurrent relationship with retrospective reports of vigorous physical activity. Study 2 attempted to replicate these results, also testing the internal structure of the MTF‐S and examining whether higher MTF‐S scores were found in participants scoring more highly on a screening test for eating disorder.MethodsIn Study 1, 626 participants completed the MTF‐PA online and reported minutes of activity in the previous week. In Study 2, 313 participants undertook an online survey that also included the MTF‐S and the Eating Attitudes Test (EAT‐26).ResultsThe studies replicated acceptable fit for the four‐factor structure on the MTF‐PA and MTF‐S. Significant associations of the MTF‐PA with recent vigorous activity and of the MTF‐S with EAT‐26 scores were seen, although associations were stronger in Study 1.ConclusionsStrong preliminary support for both the MTF‐PA and MTF‐S was obtained, although more data on their predictive validity are needed. Associations of the MTF‐S with potential eating disorder illustrate that high scores may not always be beneficial to health maintenance.
COVID‐19: Concerns and behaviours in Croatia
Authors: Lauri Korajlija Anita , Jokic‐Begic Natasa 
Published: May 2020

ObjectivesThe COVID‐19 pandemic has created uncertainty that has heightened fear and worry worldwide, thus elevating the potential for a growth in anxiety. This study aims to examine changes in levels of COVID‐19 concern and safety behaviours among persons living in Croatia during the period in which the first COVID‐19 case was identified and when the country recorded its first fatality. These changes were examined with respect to gender and family circumstances.DesignThe repeated cross‐sectional data were conducted over two time points over the 3 weeks (N1 = 888; N2 = 966).MethodsParticipants completed online questionnaire regarding various COVID‐19 concerns and safety behaviours aimed at disease prevention.ResultsFindings demonstrate dramatic increase in concern and safety behaviours among participants during the 3 weeks between the first identified case and the first fatality. The results suggest that parents, and mothers especially, represent the most concerned group, regardless of age. People with chronic health conditions also expressed greater concern and safety behaviour than healthy participants, but with small effect size.ConclusionThese findings highlight the importance of developing clear guidelines for alleviating the negative effects on mental health through effective communication strategies that minimize fear and emphasize positive behavioural change.
Statement of contribution

What is already known on this subject?

In times of pandemic, people react with elevated levels of anxiety and some will adjust their behaviours in order to protect themselves as well as their family and friends.

Some of the measures introduced to protect the spread of the COVID‐19 disease have induced an atmosphere of fear, which in turn can lead to an increase in maladaptive anxiety and a greater burden on mental health.

What does this study add?

By conducting the research in two waves representing two critical time points in the developing COVID‐19 situation in Croatia, we were able to trace a large increase in anxiety levels and safety behaviours among the general population.

There is a discordance between those who are at most risk from serious consequences of the disease and those who are at greatest risk for maladaptive anxiety. Parents, and mothers in particular, represent the most concerned group, regardless of age.

Lockdown measures have allowed us to ensure the safety of those vulnerable for serious COVID‐19 illness. Now, we must focus on preserving the mental health of our whole community.
Capability, opportunity, and motivation to enact hygienic practices in the early stages of the COVID‐19 outbreak in the United Kingdom
Authors: Gibson Miller Jilly , Hartman Todd K. , Levita Liat , Martinez Anton P. , Mason Liam , McBride Orla , McKay Ryan , Murphy Jamie , Shevlin Mark , Stocks Thomas V. A. , Bennett Kate M. , Bentall Richard P. 
Published: May 2020

ObjectivesThe COVID‐19 pandemic is one of the greatest global health threats facing humanity in recent memory. This study aimed to explore influences on hygienic practices, a set of key transmission behaviours, in relation to the Capability, Opportunity, Motivation‐Behaviour (COM‐B) model of behaviour change (Michie et al., 2011).DesignData from the first wave of a longitudinal survey study were used, launched in the early stages of the UK COVID‐19 pandemic.MethodsParticipants were 2025 adults aged 18 and older, representative of the UK population, recruited by a survey company from a panel of research participants. Participants self‐reported motivation, capability, and opportunity to enact hygienic practices during the COVID‐19 outbreak.ResultsUsing regression models, we found that all three COM‐B components significantly predicted good hygienic practices, with motivation having the greatest influence on behaviour. Breaking this down further, the subscales psychological capability, social opportunity, and reflective motivation positively influenced behaviour. Reflective motivation was largely driving behaviour, with those highest in reflective motivation scoring 51% more on the measure of hygienic practices compared with those with the lowest scores.ConclusionsOur findings have clear implications for the design of behaviour change interventions to promote hygienic practices. Interventions should focus on increasing and maintaining motivation to act and include elements that promote and maintain social support and knowledge of COVID‐19 transmission. Groups in particular need of targeting for interventions to increase hygienic practices are males and those living in cities and suburbs.
Exposure to coronavirus news on mainstream media: The role of risk perceptions and depression
Authors: Olagoke Ayokunle A. , Olagoke Olakanmi O. , Hughes Ashley M. 
Published: May 2020

ObjectiveThe mainstream media tend to rely on news content that will increase risk perceptions of pandemic outbreaks to stimulate public response and persuade people to comply with preventive behaviours. The objective of this study was to examine associations between exposure to coronavirus disease (COVID‐19) news, risk perceptions, and depressive symptoms.MethodsCross‐sectional data were collected from 501 participants who were ≥18 years. Exposure to COVID‐19 news was assessed as our exposure variable. We screened for depression (outcome variable) with the Patient Health Questionnaire and examined the roles of risk perceptions. Multiple linear regressions and mediation analysis with 1000 bootstrap resamples were conducted.ResultsParticipants were 55.29% female, 67.86% White with mean age 32.44 ± 11.94 years. After controlling for sociodemographic and socio‐economic factors, news exposure was positively associated with depressive symptoms β = .11; 95% confidence interval (95%CI) = 0.02–0.20. Mediation analysis showed that perceived vulnerability to COVID‐19 mediated 34.4% of this relationship (β = .04; 95%CI = 0.01–0.06).ConclusionPerceived vulnerability to COVID‐19 can serve as a pathway through which exposure to COVID‐19 news on mainstream media may be associated with depressive symptoms. Based on our findings, we offered recommendations for media–health partnership, practice, and research.
Analysis of the implementation level of best practices to facilitate the transition of young people with intellectual disabilities from childhood to adulthood in the Basque Country
Authors: Yurrebaso Atutxa Garazi , Martínez‐Rueda Natxo , Galarreta Lasa Javier 
Published: May 2020

Accessible summary

The literature has identified practices that should be implemented by transitional educational programmes.

We asked professionals in schools and visited three schools to identify if these best practices are being applied.

Although these best practices are being realised partially, there are differences between the opinions of professionals and the practices of centres.

The main differences are related to individualised planning, participation of families, and coordination between centres.

AbstractBackgroundAlthough studies have long identified the practices that must be included in transition programmes to improve the outcomes for young people with intellectual disabilities when becoming adults, less information is available regarding the degree to which those best practices are being developed and/or implemented.Materials and methodsThis exploratory research assesses the implementation level of those best practices in a school programme to facilitate the transition to adult life in the Basque Country, Spain. The opinions of professionals were asked through an ad hoc questionnaire, and a case study of three schools was conducted through observation, documentation analysis, interviews and focus groups.Results and discussionThe professionals were found to have a positive opinion of the implementation degree of the best practices, except for the inclusion dimension. Although analysing the cases partially confirmed this opinion, contradictions emerge as these best practices cannot always be identified in the running of schools. The dimensions with major discrepancy are related to the individualised transition planning, family involvement and interagency collaboration.ConclusionDespite having identified best practices in all dimensions, delving deep into the professionals' understanding concerning best practices is crucial.
Reconstruction of the Cenozoic deformation of the Bohai Bay Basin, North China
Authors: Zhu Yinbing , Liu Shaofeng , Zhang Bo , Gurnis Michael , Ma Pengfei 
Published: May 2020

AbstractA well‐constrained plate deformation model may lead to an improved understanding of sedimentary basin formation and the connection between subduction history and over‐riding plate deformation. Building quantitative models of basin kinematics and deformation remains challenging often due to the lack of comprehensive constraints. The Bohai Bay Basin (BBB) is an important manifestation of the destruction of the North China Craton, and records the plate kinematic history of East Asia during the Cenozoic. Although a number of interpretations of the formation of the BBB have been proposed, few quantitative basin reconstruction models have been built to test and refine previous ideas. Here, we developed a quantitative deformation reconstruction of the BBB constrained with balanced cross‐sections and structural, stratigraphic and depositional age data. Our reconstruction suggests that the basin formation process was composed of three main stages: Paleocene‐early Eocene (65–42 Ma) extension initiation, middle Eocene‐early Oligocene (42–32.8 Ma) extension climax and post‐Oligocene (32.8–0 Ma) post‐extensional subsidence. The deformation of the BBB is spatially heterogeneous, and its velocity directions rotated clockwise during the basin formation process. The reconstruction supports the interpretation that the BBB formed via strike‐slip faulting and orthogonal extension and that the basin is classified as a composite extensional‐transtensional basin. We argue that the clockwise rotation of the basin velocity field was driven by the counter‐clockwise rotation in the direction of Pacific Plate subduction. The kinematics of the BBB imply that the Pacific Plate may have been sufficiently coupled to the over‐riding East Asian Plate during the critical period of Pacific Plate reorganization. The new reconstruction provides a quantitative basis for studies of deformation processes not only in the vicinity of the BBB, but also more broadly throughout East Asia.
Biasing human epidermal growth factor receptor 4 (HER4) tyrosine kinase signaling with antibodies: Induction of cell death by antibody‐dependent HER4 intracellular domain trafficking
Authors: Lanotte Romain , Garambois Véronique , Gaborit Nadège , Larbouret Christel , Musnier Astrid , Martineau Pierre , Pèlegrin André , Chardès Thierry 
Published: May 2020

AbstractHuman epidermal growth factor receptor 4 (HER4) isoforms have oncogenic or tumor suppressor functions depending on their susceptibility to proteolytic cleavage and HER4 intracellular domain (4ICD) translocation. Here, we report that the neuregulin 1 (NRG1) tumor suppressor mechanism through the HER4 JMa/CYT1 isoform can be mimicked by the agonist anti‐HER4 Ab C6. Neuregulin 1 induced cleavage of poly(ADP‐ribose) polymerase (PARP) and sub‐G1 DNA fragmentation, and also reduced the metabolic activity of HER3−/HER4+ cervical (C‐33A) and ovarian (COV318) cancer cells. This effect was confirmed in HER4 JMa/CYT1‐, but not JMa/CYT2‐transfected BT549 triple‐negative breast cancer cells. Neuregulin 1 favored 4ICD cleavage and retention in mitochondria in JMa/CYT1‐transfected BT549 cells, leading to reactive oxygen species (ROS) production through mitochondrial depolarization. Similarly, the anti‐HER4 Ab C6, which binds to a conformational epitope located on a.a. 575‐592 and 605‐620 of HER4 domain IV, induced 4ICD cleavage and retention in mitochondria, and mimicked NRG1‐mediated effects on PARP cleavage, ROS production, and mitochondrial membrane depolarization in cancer cells. In vivo, C6 reduced growth of COV434 and HCC1187 tumor cell xenografts in nude mice. Biasing 4ICD trafficking to mitochondria with anti‐HER4 Abs to mimic NRG1 suppressor functions could be an alternative anticancer strategy.
Suppressed immune profile in children with combined type 1 diabetes and celiac disease
Authors: Tompa A , Åkesson K , Karlsson S , Faresjö M 
Published: May 2020

SummaryChildren diagnosed with a combination of type 1 diabetes (T1D) and celiac disease (CD) show a dysregulated T helper type 1 (Th1)/Th17 response. Besides the cellular involvement, several soluble immune markers are involved in the autoimmune process of both T1D and CD. Only few studies have examined the peripheral pattern of different cytokines, chemokines and acute-phase proteins (APP) in children with combined T1D and CD. To our knowledge, no studies have evaluated the serum levels of adipocytokines and matrix metalloproteinases (MMPs) in this context. The purpose of the present study was to acquire more knowledge and to gain deeper understanding regarding the peripheral immunoregulatory milieu in children with both T1D and CD. The study included children diagnosed with both T1D and CD (n = 18), children with T1D (n = 27) or CD (n = 16) and reference children (n = 42). Sera were collected and analysis of 28 immune markers (cytokines, chemokines, APPs, adipocytokines and MMPs) was performed using the Luminex technique. The major findings showed that children with a double diagnosis had lower serum levels of interleukin (IL)-22, monocyte chemoattractant protein (MIP)-1α, monocyte chemoattractant protein (MCP)-1, procalcitonin, fibrinogen, visfatin and matrix metalloproteinase (MMP)-2. These results indicate a suppressed immune profile in children with combined T1D and CD, including Th17 cytokines, chemokines, APPs, adipocytokines and MMPs. We conclude that, besides cytokines and chemokines, other immune markers, e.g. APPs, adipocytokines and MMPs, are of importance for further investigations to elucidate the heterogeneous immune processes present in patients diagnosed with T1D in combination with CD.
Pathological role of excessive DNA as a trigger of keratinocyte proliferation in psoriasis
Authors: Luo Y , Hara T , Kawashima A , Ishido Y , Suzuki S , Ishii N , Kambara T , Suzuki K 
Published: May 2020

SummaryPsoriasis is characterized by excessive growth and aberrant differentiation of epidermal keratinocytes due to persistent inflammation. However, the underlying mechanism that triggers immune activation in psoriasis is not clear. In this study, we explored excessive DNA as a potential trigger of psoriasis using cultured human keratinocytes and psoriatic skin tissues. We demonstrated that human genomic DNA fragments induced tumour necrosis factor (TNF)-α expression, hyperproliferation and over-expression of heparin-binding epidermal-like growth factor (HB-EGF) and transforming growth factor (TGF)-α, accompanied by defective expression of keratins 1 and 10 in cultured normal human epidermal keratinocytes, which have a similar phenotype to that of keratinocytes in psoriatic skin lesions. In psoriatic lesions, we found high levels of double-stranded (ds)DNA fragments, accompanying keratinocytes expressing Ki-67, HB-EGF and TNF-α. In addition, we showed that 1,25-dihydroxyvitamin D3 inhibited genomic DNA fragment-induced TNFA and interleukin-1β (IFNB) expression in human keratinocytes, and an intact function of cathelicidin anti-microbial peptide (CAMP) was required for this effect. These results suggest that excessive dsDNA fragments probably act as a risk factor for immune activation in psoriasis, and the active form of vitamin D can prevent genomic DNA-mediated skin inflammation via CAMP.