bluuebunny/crossref_metadata_2025 huggingface dataset:
A service for non-offending partners of male sexual offenders
Authors: Duff Simon , Wakefield Nick , Croft Aimee , Perry Lorraine , Valavanis Sophie , Wright Lisa
Published: September 2017

Purpose

The purpose of this paper is to present a case study of a novel service for the non-offending partners (NOPs) of men who have sexually offended against children.

Design/methodology/approach

The paper examines the rationale for the current service and the preliminary qualitative data that reflect how NOPs experience the group innovations.

Findings

Interviews and previous qualitative analyses demonstrate both the positive changes that the NOP programme supports regarding child protections skills and the value that NOPs perceive in incorporating male therapists and male offenders into the process.

Research limitations/implications

Given these recent changes to the NOP group, and the small group sizes, the ability to examine how the NOPs perceive these innovations, the personal impact they have on change in NOPs, and more importantly, the impact on recidivism and reduction of further harm to children are yet to be fully investigated and these are central questions for the service to ensure that it offers a valid and reliable intervention programme and limits the extent to which the programme can be generalised. Further research will plug this gap.

Practical implications

The service offers new challenges for NOPs with the aim of making them better understand offending against children, their role in protecting children, and ultimately the protection of children in general. This may act as a model for the development of future services for these individuals.

Originality/value

There are few programmes aimed at providing support and intervention for an often marginalised group of individuals, the female NOPs of men who have sexually offended against children. This programme includes new approaches to working with the women providing them with new sources of support and insight.
Policing registered sex offenders
Authors: Kewley Stephanie
Published: September 2017

Purpose

The purpose of this paper is to outline current police risk assessment and management practice when working with those convicted of sexual offences. The paper introduces the newly implemented Active Risk Management System (ARMS), a risk- and strengths-based tool used by the police across England and Wales.

Design/methodology/approach

A brief review of the literature and current practice is discussed.

Findings

The paper notes that in order for practitioners to work in a context of rehabilitation and reintegration, particularly one that supports clients convicted of sexual offending, there is a real need for practitioners to have the skills and experiences to work with this group. They also need to hold core values that support the notion of change and they ought to be fully supported through formal supervision and training.

Practical implications

Following are the practical implications of this paper: ∙training ought to be regular and ongoing; formal supervision sessions should be made available for all ARMS assessors; assessors ought to be assessed and observed in practice; and performance measures must be related to the quality and effectiveness of the design and implementation of risk management plans rather than the quantity of plans or home visits.

Originality/value

Very little has been written about this unique group of police practitioners who work to assess and manage people with sexual convictions. Even less is known of the effectiveness and applicability of the ARMS tool. Thus, this review is of value to academic and practitioner audiences.
Student-led leadership training for undergraduate healthcare students
Authors: Sheriff Ibrahim Hasanyn Naim , Ahmed Faheem , Jivraj Naheed , Wan Jonathan C.M. , Sampford Jade , Ahmed Na’eem
Published: September 2017

Purpose

Effective clinical leadership is crucial to avoid failings in the delivery of safe health care, particularly during a period of increasing scrutiny and cost-constraints for the National Health Service (NHS). However, there is a paucity of leadership training for health-care students, the future leaders of the NHS, which is due in part to overfilled curricula. The purpose of this study was to assess the impact of student-led leadership training for the benefit of fellow students.

Design/methodology/approach

To address this training gap, a group of multiprofessional students organised a series of large-group seminars and small-group workshops given by notable health-care leaders at a London university over the course of two consecutive years.

Findings

The majority of students had not previously received any formal exposure to leadership training. Feedback post-events were almost universally positive, though students expressed a preference for experiential teaching of leadership. Working with university faculty, an inaugural essay prize was founded and student members were given the opportunity to complete internships in real-life quality improvement projects.

Originality/value

Student-led teaching interventions in leadership can help to fill an unmet teaching need and help to better equip the next generation of health-care workers for future roles as leaders within the NHS.
Social enterprise in Israel: the swinging pendulum between collectivism and individualism
Authors: Abbou Inbal , Gidron Benjamin , Buber-Ben David Noga , Greenberg Yael , Monnickendam-Givon Yisca , Navon Aya
Published: September 2017

Purpose

The purpose of this paper is twofold: to outline the historical and current contextual forces behind the development of the social enterprise movement in Israel and to analyze the different models identified by the research team along which social enterprises are formed at present.

Design/methodology/approach

The study was part of the International Comparative Social Enterprise Models (ICSEM) Project and the methodology used in the analysis of the models was the one used in the international comparison. It entailed the analysis of three to five case studies within each model, which were analyzed along three major dimensions: the economic basis of the enterprise, its social objectives and its governance structure.

Findings

The findings suggest that social enterprises in Israel develop along four major models, all within existing different incorporation systems; these are nonprofit organizations, privately owned business enterprises, cooperatives and public-sector frameworks. On the basis of the case studies analyzed, it was possible to identify specific characteristic configurations of the three dimensions (economic/social/governance) that were at the basis of the model and guided it.

Originality/value

The study is the first of its kind to present a broad picture of the developing social enterprise scene in Israel and as such can clearly inform and guide both researchers and policymakers in their future work on the development of the social enterprise phenomenon in the country.
Mapping social enterprise models: some evidence from the “ICSEM” project
Authors: Defourny Jacques , Nyssens Marthe
Published: September 2017

Purpose

The purpose of this paper is to demonstrate that it is feasible to theoretically and empirically build an international typology of social enterprise (SE) models. The authors first rely on their previous work (Defourny and Nyssens, 2017), suggesting that the concept of “interest principles” can serve as a cornerstone in such perspective. This concept, when combined with that of SEs’ “resource mixes”, allows to design an analytical tool that shows from which “matrices” and through which “trajectories” several distinct SE models can emerge, namely, the “non-profit entrepreneurial model”, the “social cooperative model”, the “social business model” and the “public sector model”.

Design/methodology/approach

This paper combines deductive and inductive approaches. In a deductive perspective, the authors build upon the analytical framework proposed by Gui (1991) to identify capital interest, mutual interest and general interest as key driving forces and fundamental motives in the overall economy. To confront their theoretical construction and their tentative typology of SE models with field realities, the authors also adopt an inductive approach, relying on bottom-up research strategies developed in the seven “ICSEM country contributions” forming this special issue.

Findings

At first view, mapping exercises of SE categories in the seven countries seem to highlight a high degree of heterogeneity. However, a closer analysis of these apparently diverging contributions clearly suggests that the four major SE models derived from the authors’ theoretical framework find significant empirical support in most—if not all—countries.

Originality/value

Although major statistical work to test the authors’ typology of SE models remains to be carried out, mainly through the exploitation of the international ICSEM database (which covers over 700 SEs from more than 40 countries), this paper represents a first—although limited—attempt to collect empirical evidence for testing this typology.
Dynamic, spatial models of parasite transmission in wildlife: Their structure, applications and remaining challenges
Authors: White Lauren A. , Forester James D. , Craft Meggan E.
Published: September 2017

Individual differences in contact rate can arise from host, group and landscape heterogeneity and can result in different patterns of spatial spread for diseases in wildlife populations with concomitant implications for disease control in wildlife of conservation concern, livestock and humans. While dynamic disease models can provide a better understanding of the drivers of spatial spread, the effects of landscape heterogeneity have only been modelled in a few well‐studied wildlife systems such as rabies and bovine tuberculosis. Such spatial models tend to be either purely theoretical with intrinsic limiting assumptions or individual‐based models that are often highly species‐ and system‐specific, limiting the breadth of their utility.

Our goal was to review studies that have utilized dynamic, spatial models to answer questions about pathogen transmission in wildlife and identify key gaps in the literature. We begin by providing an overview of the main types of dynamic, spatial models (e.g., metapopulation, network, lattice, cellular automata, individual‐based and continuous‐space) and their relation to each other. We investigate different types of ecological questions that these models have been used to explore: pathogen invasion dynamics and range expansion, spatial heterogeneity and pathogen persistence, the implications of management and intervention strategies and the role of evolution in host–pathogen dynamics.

We reviewed 168 studies that consider pathogen transmission in free‐ranging wildlife and classify them by the model type employed, the focal host–pathogen system, and their overall research themes and motivation. We observed a significant focus on mammalian hosts, a few well‐studied or purely theoretical pathogen systems, and a lack of studies occurring at the wildlife‐public health or wildlife–livestock interfaces.

Finally, we discuss challenges and future directions in the context of unprecedented human‐mediated environmental change. Spatial models may provide new insights into understanding, for example, how global warming and habitat disturbance contribute to disease maintenance and emergence. Moving forward, better integration of dynamic, spatial disease models with approaches from movement ecology, landscape genetics/genomics and ecoimmunology may provide new avenues for investigation and aid in the control of zoonotic and emerging infectious diseases.
Dietary niche variation and its relationship to lizard population density
Authors: Novosolov Maria , Rodda Gordon H. , Gainsbury Alison M. , Meiri Shai
Published: September 2017

Insular species are predicted to broaden their niches, in response to having fewer competitors. They can thus exploit a greater proportion of the resource spectrum. In turn, broader niches are hypothesized to facilitate (or be a consequence of) increased population densities.

We tested whether insular lizards have broader dietary niches than mainland species, how it relates to competitor and predator richness, and the nature of the relationship between population density and dietary niche breadth.

We collected population density and dietary niche breadth data for 36 insular and 59 mainland lizard species, and estimated competitor and predator richness at the localities where diet data were collected. We estimated dietary niche shift by comparing island species to their mainland relatives. We controlled for phylogenetic relatedness, body mass and the size of the plots over which densities were estimated.

We found that island and mainland species had similar niche breadths. Dietary niche breadth was unrelated to competitor and predator richness, on both islands and the mainland. Population density was unrelated to dietary niche breadth across island and mainland populations.

Our results indicate that dietary generalism is not an effective way of increasing population density nor is it result of lower competitive pressure. A lower variety of resources on islands may prevent insular animals from increasing their niche breadths even in the face of few competitors.
Inhibitory effect of the tricyclic antidepressant amitriptyline on voltage‐dependent K+ channels in rabbit coronary arterial smooth muscle cells
Authors: Li Hongliang , Shin Sung Eun , Seo Mi Seon , An Jin Ryeol , Ha Kwon‐Soo , Han Eun‐Taek , Hong Seok‐Ho , Choi Il‐Whan , Lee Dae‐Sung , Yim Mi‐Jin , Lee Jeong Min , Jung In Duk , Firth Amy L. , Han Il Yong , Park Won Sun
Published: September 2017

Amitriptyline, a tricyclic antidepressant (TCA) drug, is widely used in treatment of psychiatric disorders. However, the side effects of amitriptyline on vascular K+ channels remain to be determined. Therefore, we investigated the effect of the tricyclic antidepressant and serotonin reuptake inhibitor amitriptyline on voltage‐dependent K+ (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells, using the whole‐cell patch clamp technique. The Kv current amplitudes were inhibited by amitriptyline in a concentration‐dependent manner, with an apparent IC50 value of 2.2 ± 0.14 μmol/L and a Hill coefficient of 0.87 ± 0.03. Amitriptyline shifted the activation curve to a more positive potential, but had no significant effect on the inactivation curve, suggesting that amitriptyline altered the voltage sensitivity of Kv channels. Pretreatment with Kv1.5 and Kv1.2 channel inhibitors did not alter the inhibitory effect of amitriptyline on Kv channels. Additionally, application of train pulses (1 and 2 Hz) did not affect amitriptyline‐induced inhibition of Kv currents, which suggested that the action of amitriptyline on Kv channels was not use (state)‐dependent. From these results, we concluded that amitriptyline inhibited the channels in a concentration‐dependent, but state‐independent manner.
RhPDCD5 combined with dexamethasone increases antitumor activity in multiple myeloma partially via inhibiting the Wnt signalling pathway
Authors: Cheng Qian , Liu Liping , Fu Yunfeng , Zhang Yanan , Yang Ye , Liu Jing
Published: September 2017

Multiple myeloma (MM) is one of the most common hematological malignancies and characterized by the clonal accumulation of malignant plasma cells. Significant progress has been made in MM treatment recently, while MM still remains incurable. Our previous studies showed that the recombined human programmed cell death 5 (rhPDCD5) can promote MM apoptosis induced by dexamethasone (Dex). Here, we expanded the findings by showing that the rhPDCD5 alone could not induce an obvious growth inhibition of U266 cells (a MM cell line). Of note, with the combination of dexamethasone (Dex), the growth of MM cells was significantly inhibited and accompanied with the cell cycle arrest in G0/G1. For mechanism study, we found that the combination treatment of rhPDCD5 plus Dex downregulated the mRNA and protein expressions of Wnt effectors including β‐catenin, β‐catenin (Ser675), TCF4, survivin and c‐Myc when compared to Dex only. Moreover, the activation of WNT pathway induced by LiCl can also be inhibited by this combination treatment. Taken together, our study demonstrated that the combination of rhPDCD5 and Dex can suppress the proliferation of multiple myeloma cells partially via inhibiting the WNT signalling pathway.
Does Spatial Dependence Affect the Intention to Make Land Available for Bioenergy Crops?
Authors: Skevas Theodoros , Skevas Ioannis , Swinton Scott M.
Published: September 2017

We find spatial dependence in landowners’ stated intentions to make land available for bioenergy crops. Our data are generated from a contingent valuation survey of 599 owners of marginal land in southern Michigan. Employing a Bayesian framework and using these spatially explicit data, we estimate and compare non‐spatial probit and spatial Durbin probit models to examine the presence of spatial dependence in land rental intentions. Results show that intentions to rent land for bioenergy crop production are spatially dependent. This spatial dependence arises both from the land supply intentions of nearby landowners and from spatial spillover effects of landowner characteristics and attitudes towards environmental amenities and the disamenities of land rental. We show that ignoring spatial dependence in the intentions of neighbouring landowners to participate in land rental markets for bioenergy feedstocks can lead to distortions that underestimate total effects. Our finding implies that studies of land use and crop supply should test for spatial interactions in order to make accurate inferences.
TESTING THE TRANSITIVITY OF REPORTED RISK PERCEPTIONS: EVIDENCE OF COHERENT ARBITRARINESS
Authors: THOMAS KYLE J. , HAMILTON BENJAMIN C. , LOUGHRAN THOMAS A.
Published: September 2017

An often implicit assumption of perceptual deterrence tests is that the elicited values pertaining to arrest risk reflect stable underlying beliefs. But researchers in other disciplines have found that reported expectations are highly susceptible to exogenous factors (e.g., anchors and question ordering), indicating that such values are somewhat arbitrary responses to probabilistic questions. At the same time, reported expectations are coherent within persons, such that respondents rank order them rationally. For deterrence, then, absolute values reported on arrest risks are likely not stable but individuals still rank order specific crimes in meaningful ways. We examine the interpretability of reported arrest risk for three possibilities: 1) Reported risks are stable probabilistic values; 2) reported risks are arbitrary and uninformative for deterrence research; or 3) reported risks display “coherent arbitrariness” with unstable values between individuals but stable rank ordering of crimes within individuals. Through the use of three random experiments of college students, our results indicate that elicited risk perceptions are arbitrary in that they are influenced by the presentation of anchors and question ordering. Nevertheless, the rank ordering of crimes within and across conditions is unaffected by the presentation of anchors, suggesting that reported risks are locally coherent within persons.
Community‐based survey of knowledge of, attitudes to and practice of colorectal cancer screening in Hong Kong
Authors: Wong Grace Ching Yin , Lee Ka Yu , Lam Kwok Fai , Fan Susan Yun Sun
Published: September 2017

OBJECTIVE

We aimed to investigate the knowledge, attitudes and practice of colorectal cancer (CRC) and screening in the community to complement the introduction of population‐based CRC screening in Hong Kong SAR, China.

METHODS

Clients attending the Family Planning Association of Hong Kong clinics from March to June 2016 were randomly invited to participate in this questionnaire survey.

RESULTS

Knowledge of CRC and screening for it was still deficient in the community. Respondents scored less than half on their knowledge of the symptoms and screening methods of CRC as well as on the local screening policy. Fewer than 30% knew that CRC can be asymptomatic and they had insufficient knowledge of primary lifestyle prevention of CRC. However, most (86.0%) would like to participate in CRC screening. The cost and trouble involved were the two main reasons given for not wanting to do so. Only 14.0% of the whole sample and 27.0% of those aged 50 years or above had undergone CRC screening irrespective of screening method. One‐fifth of those who had been screened had some abnormality, with a cancer detection rate of 2.2%. Employment, income, knowledge and perception of risk were major determinants of their decision to undergo screening.

CONCLUSIONS

To reduce the morbidity and mortality of CRC significantly, average risk and high‐risk groups should be encouraged to come forward for screening even if they are asymptomatic. Educating the population, simplifying the screening procedure and offering financial support by the government are keys to success.
The Prospective Association Between Internalizing Symptoms and Adolescent Alcohol Involvement and the Moderating Role of Age and Externalizing Symptoms
Authors: Colder Craig R. , Shyhalla Kathleen , Frndak Seth , Read Jennifer P. , Lengua Liliana J. , Hawk Larry W. , Wieczorek William F.
Published: September 2017

Background

As predicted by self‐medication theories that drinking is motivated by a desire to ameliorate emotional distress, some studies find internalizing symptoms (e.g., anxiety, depression) increase risk of adolescent drinking; however, such a risk effect has not been supported consistently. Our prior work examined externalizing symptoms as a potential moderator of the association between internalizing symptoms and adolescent alcohol use to explain some of the inconsistencies in the literature. We found that internalizing symptoms were protective against early adolescent alcohol use particularly for youth elevated on externalizing symptoms (a 2‐way interaction). Our sample has now been followed for several additional assessments that extend into young adulthood, and the current study tests whether the protective effect of internalizing symptoms may change as youth age into young adulthood, and whether this age‐moderating effect varied across different clusters of internalizing symptoms (social anxiety, generalized anxiety, and depression). Internalizing symptoms were hypothesized to shift from a protective factor to a risk factor with age, particularly for youth elevated on externalizing symptoms.

Methods

A community sample of 387 adolescents was followed for 9 annual assessments (mean age = 12.1 years at the first assessment and 55% female). Multilevel cross‐lagged 2‐part zero‐inflated Poisson models were used to test hypotheses.

Results

The most robust moderating effects were for levels of alcohol use, such that the protective effect of all internalizing symptom clusters was most evident in the context of moderate to high levels of externalizing problems. A risk effect of internalizing symptoms was evident at low levels of externalizing symptoms. With age, the risk and protective effects of internalizing symptoms were evident at less extreme levels of externalizing behavior. With respect to alcohol‐related problems, findings did not support age moderation for generalized anxiety or depression, but it was supported for social anxiety.

Conclusions

Findings highlight the importance of considering the role of emotional distress from a developmental perspective and in the context of externalizing behavior problems.
Imaging the neuroimmune response to alcohol exposure in adolescent baboons: a TSPO PET study using 18F‐DPA‐714
Authors: Saba Wadad , Goutal Sébastien , Auvity Sylvain , Kuhnast Bertrand , Coulon Christine , Kouyoumdjian Virginie , Buvat Irène , Leroy Claire , Tournier Nicolas
Published: September 2017

The effects of acute alcohol exposure to the central nervous system are hypothesized to involve the innate immune system. The neuroimmune response to an initial and acute alcohol exposure was investigated using translocator protein 18 kDa (TSPO) PET imaging, a non‐invasive marker of glial activation, in adolescent baboons. Three different alcohol‐naive adolescent baboons (3–4 years old, 9 to 14 kg) underwent 18F‐DPA‐714 PET experiments before, during and 7–12 months after this initial alcohol exposure (0.7–1.0 g/l). The brain distribution of 18F‐DPA‐714 (VT; in ml/cm3) was estimated in several brain regions using the Logan plot analysis and the metabolite‐corrected arterial input function. Compared with alcohol‐naive animals (VTbrain = 3.7 ± 0.7 ml/cm3), the regional VTs of 18F‐DPA‐714 were significantly increased during alcohol exposure (VTbrain = 7.2 ± 0.4 ml/cm3; p < 0.001). Regional VTs estimated several months after alcohol exposure (VTbrain = 5.7 ± 1.4 ml/cm3) were lower (p < 0.001) than those measured during alcohol exposure, but remained significantly higher (p < 0.001) than in alcohol‐naive animals. The acute and long‐term effects of ethanol exposure were observed globally across all brain regions. Acute alcohol exposure increased the binding of 18F‐DPA‐714 to the brain in a non‐human primate model of alcohol exposure that reflects the ‘binge drinking’ situation in adolescent individuals. The effect persisted for several months, suggesting a ‘priming’ of glial cell function after initial alcohol exposure.
Limited potential of cebranopadol to produce opioid‐type physical dependence in rodents
Authors: Tzschentke Thomas M. , Kögel Babette Y. , Frosch Stefanie , Linz Klaus
Published: September 2017

Cebranopadol is a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors. As NOP receptor activation has been shown to reduce side effects related to the activation of μ‐opioid peptide (MOP) receptors, the present study evaluated opioid‐type physical dependence produced by cebranopadol in mice and rats. In a naloxone‐precipitated withdrawal assay in mice, a regimen of seven escalating doses of cebranopadol over 2 days produced only very limited physical dependence as evidenced by very little withdrawal symptoms (jumping) even at cebranopadol doses clearly exceeding the analgesic dose range. In contrast, mice showed clear withdrawal symptoms when treated with morphine within the analgesic dose range. In the rat, spontaneous withdrawal (by cessation of drug treatment; in terms of weight loss and behavioral score) was studied after 4‐week subacute administration. Naloxone‐precipitated withdrawal (in terms of weight loss and behavioral score) was studied in the same groups of rats after 1‐week re‐administration following the spontaneous withdrawal period. In both tests, cebranopadol‐treated rats showed only few signs of withdrawal, while withdrawal effects in rats treated with morphine were clearly evident. These findings demonstrate a low potential of cebranopadol to produce opioid‐type physical dependence in rodents. The prospect of this promising finding into the clinical setting remains to be established.
A composite of exhaled LTB4, LXA4, FeNO, and FEV1 as an “asthma classification ratio” characterizes childhood asthma
Authors: Chen L.‐C. , Tseng H.‐M. , Kuo M.‐L. , Chiu C.‐Y. , Liao S.‐L. , Su K.‐W. , Tsai M.‐H. , Hua M.‐C. , Lai S.‐H. , Yao T.‐C. , Yeh K.‐W. , Wu A.‐H. , Huang J.‐L. , Huang S.‐K.
Published: September 2017

Background

Aberrant generation of eicosanoids is associated with asthma, but the evidence remains incomplete and its potential utility as biomarkers is unclear. Major eicosanoids in exhaled breath condensates (EBCs) were assessed as candidate markers for childhood asthma.

Methods

Ten exhaled eicosanoid species was evaluated using ELISA in the discovery phase, followed by prediction model‐building and validation phases.

Results

Exhaled LTB4, LTE4, PGE2, and LXA4 showed significant difference between asthmatics (N = 60) and controls (N = 20). For validation, an expanded study population consisting of 626 subjects with asthma and 161 healthy controls was partitioned into a training subset to establish a prediction model and a test sample subset for validation. Receiver operating characteristic (ROC) analyses of the training subset revealed the level of exhaled LTB4 to be the most discriminative among all parameters, including FeNO, and a composite of exhaled LTB4, LXA4, together with FeNO and FEV1, distinguishing asthma with high sensitivity and specificity. Further, the Youden index (J) indicated the cut point value of 0.598 for this composite of markers as having the strongest discriminatory ability (sensitivity = 85.2% and specificity = 83.6%). The predictive algorithm as “asthma classification ratio” was further validated in an independent test sample with sensitivity and specificity being 84.4% and 84.8%, respectively.

Conclusions

In a pediatric study population in Taiwan, the levels of exhaled LTB4, LTE4, LXA4, and PGE2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB4 and LXA4, together with FeNO and FEV1, best characterized childhood asthma.
Gendered youth strategies for inclusion in a changing society: Breaking or reproducing the local gender contract?
Authors: Stenbacka Susanne , Grubbström Ann , Forsberg Gunnel
Published: September 2017

This paper explores how place and gender relations influence young people's ways of formulating their struggles and negotiations related to education, work, family, everyday life and achievement of certain life goals. In addition, the paper examines key municipal officials’ viewpoints, opening up a space for exchange and development at the interface of policy actions and young people's embodied lives. It is shown that young men and women alike are aware of the challenge to deconstruct hegemonic notions of gender. The focus is on societal changes and young people's educational and work strategies in Dalarna, Central Sweden. Historically, this county was dependent on steel, iron and paper industries: traditionally male employment sectors. Transformation of the labour market is involving new trends and expectations. A result is that gender relations associated with place‐specific, as well as general, assumptions about masculinity and femininity are becoming increasingly fluid while their discursive strength remains.
Prediction of Drug–Drug Interaction between Tacrolimus and Principal Ingredients of Wuzhi Capsule in Chinese Healthy Volunteers Using Physiologically‐Based Pharmacokinetic Modelling
Authors: Zhang Hongyan , Bu Fengjiao , Li Lei , Jiao Zheng , Ma Guo , Cai Weimin , Zhuang Xiaomei , Lin Hai‐Shu , Shin Jae‐Gook , Xiang Xiaoqiang
Published: September 2017

Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug–drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically‐based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 was investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus were established. Finally, tacrolimus pharmacokinetics were evaluated after the combined use with schisantherin A or schisandrin A. The blood area under the curve (AUC) of tacrolimus increased 1.77‐ and 2.61‐fold after a single dose and multiple doses of schisantherin A, respectively. Meanwhile, schisandrin A inhibited tacrolimus metabolism to a smaller extent. Also, it showed that mechanism‐based inhibition (MBI) played a more important role in DDI than reversible inhibition after long‐term administration, while reversible inhibition was comparable to MBI after single‐dose administration. In conclusion, we utilized PBPK modelling to quantify the contribution of schisantherin A and schisandrin A to DDI between tacrolimus and Wuzhi capsule. This may provide more insights for the rational use of this drug combination.
The International Society for Bipolar Disorders Task Force report on pediatric bipolar disorder: Knowledge to date and directions for future research
Authors: Goldstein Benjamin I , Birmaher Boris , Carlson Gabrielle A , DelBello Melissa P , Findling Robert L , Fristad Mary , Kowatch Robert A , Miklowitz David J , Nery Fabiano G , Perez‐Algorta Guillermo , Van Meter Anna , Zeni Cristian P , Correll Christoph U , Kim Hyo‐Won , Wozniak Janet , Chang Kiki D , Hillegers Manon , Youngstrom Eric A
Published: September 2017

Objectives

Over the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings.

Methods

An international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps.

Results

Substantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold‐standard pharmacologic trials inform treatment of manic/mixed episodes, whereas fewer data address bipolar depression and maintenance/continuation treatment. Adjunctive psychosocial treatment provides a forum for psychoeducation and targets primarily depressive symptoms. Numerous neurocognitive and neuroimaging studies, and increasing peripheral biomarker studies, largely converge with prior findings from adults with BD.

Conclusions

As data have accumulated and controversy has dissipated, the field has moved past existential questions about PBD toward defining and pursuing pressing clinical and scientific priorities that remain. The overall body of evidence supports the position that perceptions about marked international (US vs elsewhere) and developmental (pediatric vs adult) differences have been overstated, although additional research on these topics is warranted. Traction toward improved outcomes will be supported by continued emphasis on pathophysiology and novel therapeutics.
VPAC1 and VPAC2 receptor activation on GABA release from hippocampal nerve terminals involve several different signalling pathways
Authors: Cunha‐Reis Diana , Ribeiro Joaquim Alexandre , de Almeida Rodrigo F M , Sebastião Ana M
Published: September 2017

Background and Purpose

Vasoactive intestinal peptide (VIP) is an important modulator of hippocampal synaptic transmission that influences both GABAergic synaptic transmission and glutamatergic cell excitability through activation of VPAC1 and VPAC2 receptors. Presynaptic enhancement of GABA release contributes to VIP modulation of hippocampal synaptic transmission.

Experimental Approach

We investigated which VIP receptors and coupled transduction pathways were involved in VIP enhancement of K+‐evoked [3H]‐GABA release from isolated nerve terminals of rat hippocampus.

Key Results

VIP enhancement of [3H]‐GABA release was potentiated in the presence of the VPAC1 receptor antagonist PG 97‐269 but converted into an inhibition in the presence of the VPAC2 receptor antagonist PG 99‐465, suggesting that activation of VPAC1 receptors inhibits and activation of VPAC2 receptors enhances, GABA release. A VPAC1 receptor agonist inhibited exocytotic voltage‐gated calcium channel (VGCC)‐dependent [3H]‐GABA release through activation of protein Gi/o, an effect also dependent on PKC activity. A VPAC2 receptor agonist enhanced both exocytotic VGCC‐dependent release through protein Gs‐dependent, PKA‐dependent and PKC‐dependent mechanisms and GABA transporter 1‐mediated [3H]‐GABA release through a Gs protein‐dependent and PKC‐dependent mechanism.

Conclusions and Implications

Our results show that VPAC1 and VPAC2 VIP receptors have opposing actions on GABA release from hippocampal nerve terminals through activation of different transduction pathways. As VPAC1 and VPAC2 receptors are located in different layers of Ammon's horn, our results suggest that these VIP receptors underlie different modulation of synaptic transmission to pyramidal cell dendrites and cell bodies, with important consequences for their possible therapeutic application in the treatment of epilepsy.
Ensemble docking to difficult targets in early‐stage drug discovery: Methodology and application to fibroblast growth factor 23
Authors: Velazquez Hector A. , Riccardi Demian , Xiao Zhousheng , Quarles Leigh Darryl , Yates Charless Ryan , Baudry Jerome , Smith Jeremy C.
Published: September 2017

Ensemble docking is now commonly used in early‐stage in silico drug discovery and can be used to attack difficult problems such as finding lead compounds which can disrupt protein–protein interactions. We give an example of this methodology here, as applied to fibroblast growth factor 23 (FGF23), a protein hormone that is responsible for regulating phosphate homeostasis. The first small‐molecule antagonists of FGF23 were recently discovered by combining ensemble docking with extensive experimental target validation data (Science Signaling, 9, 2016, ra113). Here, we provide a detailed account of how ensemble‐based high‐throughput virtual screening was used to identify the antagonist compounds discovered in reference (Science Signaling, 9, 2016, ra113). Moreover, we perform further calculations, redocking those antagonist compounds identified in reference (Science Signaling, 9, 2016, ra113) that performed well on drug‐likeness filters, to predict possible binding regions. These predicted binding modes are rescored with the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) approach to calculate the most likely binding site. Our findings suggest that the antagonist compounds antagonize FGF23 through the disruption of protein–protein interactions between FGF23 and fibroblast growth factor receptor (FGFR).
Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors
Authors: Skibiński Robert , Czarnecka Kamila , Girek Małgorzata , Bilichowski Ireneusz , Chufarova Nina , Mikiciuk‐Olasik Elżbieta , Szymański Paweł
Published: September 2017

New synthesized series of 9‐amino‐1,2,3,4‐tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β‐amyloid aggregation. All novel molecules 3a–3i interacted with both cholinesterases—acetylcholinesterase and butyrylcholinesterase—delivered nanomolar IC50 values. The structure–activity relationship showed that N‐butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N‐ethyl and N‐propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC50 = 31.2 nm), and it was more active than reference drug, tacrine (IC50 = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC50 = 8.0 nm), also higher than tacrine (IC50 = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β‐amyloid aggregation (at the concentration 10 μm—24.96% of inhibition, 25 μm—72%, 50 μm—78.44%, and 100 μm—84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.
CD4+ T helper cells and regulatory T cells in active lupus nephritis: an imbalance towards a predominant Th1 response?
Authors: Mesquita D , Kirsztajn G Mastroianni , Franco M F , Reis L A , Perazzio S F , Mesquita F V , da Silva Ferreira V , Andrade L E Coelho , Silva de Souza A W
Published: September 2017

The objective of this study was to evaluate the frequency of CD4+ T cell subsets in peripheral blood mononuclear cells (PBMC), urine and renal tissue from patients with lupus nephritis (LN). PBMC and urinary cells were collected from 17 patients with active LN, 20 disease controls (DC) with primary glomerulonephritis and 10 healthy controls (HC) and were analysed by flow cytometry with markers for T helper type 1 (Th1), Th2, Th17 and regulatory T cells (Treg) cells. T cell subsets were assessed by immunohistochemistry from LN biopsy specimens from 12 LN patients. T cell subtypes in PBMC were re-evaluated at 6 months of therapy. CD4+ T cells were decreased in PBMC in LN compared with DC and HC (P = 0·0001). No differences were observed in urinary CD4+ T cell subsets between LN and DC. The frequency of urinary Th17 cells was higher in patients with non-proliferative than in proliferative LN (P = 0·041). CD3+ and T-box 21 (Tbet+) cells were found in glomeruli and interstitium of LN patients, while forkhead box protein 3 (FoxP3), retinoid-related orphan receptor gamma (ROR-γ) and GATA binding protein 3 (GATA-3) were present only in glomeruli. Th1 cells in PBMC were correlated negatively with urinary Th1 cells (Rho = –0·531; P = 0·028) and with Tbet in renal interstitium (Rho = –0·782; P = 0·004). At 6 months, LN patients showed an increase in Th17 cells in PBMC. In conclusion, the inverse association between Th1 cells from PBMC and urinary/renal tissue indicate a role for Th1 in LN pathophysiology. Urinary Th17 cells were associated with less severe LN, and Th17 increased in PBMC during therapy. Urinary CD4+ T cells were not different between LN and DC.
Conflicts in Family Relations, Children's Emotions and Agency
Authors: Notko Marianne , Sevón Eija
Published: September 2017

What kind of conflicts and tensions do children experience with other children and adults in the family? Content analysis of 32 thematic interviews with 10‐ to 13‐year‐old children revealed that while conflicts often concern daily actions, tasks and routines, they also relate to decision‐making and fair treatment or to matters threatening the child's sense of emotional security. Parental conflicts and conflicts in child–parent relationships often arouse negative emotions that lead children to suppress their agency. However, conflicts, particularly those between siblings, may also open up possibilities for negotiation and agency.
Cost‐utility analysis of direct ventricular assist device vs double bridges to heart transplantation in patients with refractory heart failure
Authors: Chang Hsiao‐Huang , Chen Po‐Lin , Chen I‐Ming , Kuo Tzu‐Ting , Weng Zen‐Chung , Huang Pei‐Jung , Wu Nai‐Yuan , Cheng Ching‐Li
Published: September 2017

Object

This study compared the cost‐utility of direct ventricular assist device (VAD) vs double bridges, extracorporeal membrane oxygenation (ECMO) before VAD, to heart transplantation in patients with refractory heart failure.

Materials and Methods

From a health payer perspective, a Markov model was developed. The cycle length was 1 month, and the time horizon was a lifetime. Probabilities and direct cost data were calculated from a nationwide claim database. Utility inputs were adopted from published sources. The utility was expressed as quality‐adjusted life years (QALYs). Both costs and utility were discounted by an annual rate of 3%. Deterministic and probabilistic sensitivity analyses were performed to test the stability of the model.

Results

The direct VAD group had less lifetime costs (USD 95 910 vs USD 129 516) but higher lifetime QALYs than the double bridges group (1.73 vs 0.89). The sensitivity analysis revealed that the direct VAD group consistently had lower cost and higher QALYs during all variations in model parameters. The probability that direct VAD was cost‐effective exceeded 75% at any levels of willing‐to‐pay.

Conclusion

From a health insurance payer perspective, direct VAD bridge to heart transplantation appeared to be more cost‐effective than double bridges in patients with refractory heart failure.
Using individual functional channels of interest to study cortical development with fNIRS
Authors: Powell Lindsey J. , Deen Ben , Saxe Rebecca
Published: September 2017

Functional near‐infrared spectroscopy (fNIRS) is a noninvasive neuroimaging technique that could be uniquely effective for investigating cortical function in human infants. However, prior efforts have been hampered by the difficulty of aligning arrays of fNIRS optodes placed on the scalp to anatomical or functional regions of underlying cortex. This challenge can be addressed by identifying channels of interest in individual participants, and then testing the reliability of those channels' response profiles in independent data. Using this approach, cortical regions with preferential responses to faces versus scenes, and to scenes versus faces, were observed reliably in both adults and infants. By contrast, standard analysis techniques did not reliably identify significant responses to both categories in either age group. These results reveal scene‐responsive regions, and confirm face‐responsive regions, in preverbal infants. More generally, the analysis approach will be a robust and sensitive tool for future characterization of the early functional development of the human brain.
Digital disruption? Maternal mobile device use is related to infant social‐emotional functioning
Authors: Myruski Sarah , Gulyayeva Olga , Birk Samantha , Pérez‐Edgar Koraly , Buss Kristin A. , Dennis‐Tiwary Tracy A.
Published: September 2017

Mobile device use has become increasingly prevalent, yet its impact on infant development remains largely unknown. When parents use mobile devices in front of infants, the parent is physically present but most likely distracted and unresponsive. Research using the classic Still Face Paradigm (SFP) suggests that parental withdrawal and unresponsiveness may have negative consequences for children's social‐emotional development. In the present study, 50 infants aged 7.20 to 23.60 months (M = 15.40, SD = 4.74) and their mothers completed a modified SFP. The SFP consisted of three phases: free play (FP; parent and infant play and interact), still face (SF; parent withdraws attention and becomes unresponsive), and reunion (RU; parent resumes normal interaction). The modified SFP incorporated mobile device use in the SF phase. Parents reported on their typical mobile device use and infant temperament. Consistent with the standard SFP, infants showed more negative affect and less positive affect during SF versus FP. Infants also showed more toy engagement and more engagement with mother during FP versus SF and RU. Infants showed the most social bids during SF and more room exploration in SF than RU. More frequent reported mobile device use was associated with less room exploration and positive affect during SF, and less recovery (i.e., engagement with mother, room exploration positive affect) during RU, even when controlling for individual differences in temperament. Findings suggest that the SFP represents a promising theoretical framework for understanding the impact of parent's mobile device use on infant social‐emotional functioning and parent–infant interactions.