Female patient violence experienced by female qualified nurses working in an inpatient psychiatric department.

Whilst there is an increasing prevalence of healthcare staff facing aggression, psychiatric nurses are thought to be most at risk; with such events being a hazard to their physical, emotional and psychological health. This study explored how patient violence is experienced by qualified nurses employed in an in-patient psychiatric facility in the Kingdom of Saudi Arabia (KSA). As male and female patients and nurses are segregated in Saudi healthcare settings, this study focused on female patient violence against female psychiatric nurses. Both the immediate and more long-term impacts were explored, together with approaches that could potentially facilitate avoiding, reducing and managing aggression within the work setting. The study adopted a qualitative descriptive design and used purposive sampling to recruit nine psychiatric nurses working in an in-patient setting, from a single KSA medical facility. Inclusion criteria required participants to be licensed, registered nurses, who, during the last 10 years, had worked in an acute in-patient psychiatric ward for adult females, and to have experienced some form of patient aggression. Semi-structured, one-to-one interviews were used to gather data, which was then subjected to thematic analysis. Two dominant themes were identified: (i) occurrence of violence and (ii) determination of violence. It was concluded that female psychiatric nurses were adversely affected by aggression towards them from female patients. Although the nurses considered this behaviour to be part of their nursing role, they reported minimal support from institutional managers, peers and their relatives.

A Tale of Two Stories: A Narrative of Bulimia in a Research Study of Anorexia, and the Dilemmas of a Novice Researcher.

The purpose of this paper is two-fold: Firstly, it reports on one man's experience of bulimia. After being interviewed it became evident that he did not meet the inclusion criteria for the study, which was focussed on anorexia in men. Secondly, the paper explores the implications for a novice researcher of including someone in a study who does not meet the inclusion criteria. The researcher's story reflects upon the implications of self-doubt when embarking upon sensitive research, and the morality of holding onto a rogue participant's story. It offers others an opportunity to consider and learn from this experience.

Molecular basis of ß-arrestin coupling to formoterol-bound ß1-adrenoceptor.

The ß1-adrenoceptor (ß1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of ß-arrestin 1 (ßarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism3-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the ß1AR-ßarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound ß1AR coupled to the G-protein-mimetic nanobody6 Nb80. ßarr1 couples to ß1AR in a manner distinct to that7 of Gs coupling to ß2AR-the finger loop of ßarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in ßarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. ß1AR coupled to ßarr1 shows considerable differences in structure compared with ß1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of ß1AR, and find that formoterol has a lower affinity for the ß1AR-ßarr1 complex than for the ß1AR-Gs complex. The structural differences between these complexes of ß1AR provide a foundation for the design of small molecules that could bias signalling in the ß-adrenoceptors.

Disappearing in a Female World: Men's Experiences of Having an Eating Disorder (ED) and How It Impacts Their Lives.

The number of men diagnosed with anorexia has increased, men now representing 25% of those with eating disorders (EDs). Research has mainly been quantitative and female focused, with only two qualitative studies exploring the experiences of men. This study focused on the lived experiences of men diagnosed with an ED, and its impact on 'everyday' aspects of their lives. Qualitative research adopting narrative interviews was conducted with seven men aged 23-34 years old. Narrative analysis was used to interpret each individual story, with thematic analysis used to explore commonalities across all seven narratives. Four themes were identified, 1) The Final John Doe; 2) Help! I need somebody - Bedlam revisited; 3) Masculinity; 4) Not Working 9 to 5. Narratives highlight the need for further research if men are to receive appropriate mental health care and better understanding and acceptance on the part of society, service providers, employers and men themselves.

Molecular basis for high-affinity agonist binding in GPCRs.

G protein-coupled receptors (GPCRs) in the G protein-coupled active state have higher affinity for agonists as compared with when they are in the inactive state, but the molecular basis for this is unclear. We have determined four active-state structures of the ß1-adrenoceptor (ß1AR) bound to conformation-specific nanobodies in the presence of agonists of varying efficacy. Comparison with inactive-state structures of ß1AR bound to the identical ligands showed a 24 to 42% reduction in the volume of the orthosteric binding site. Potential hydrogen bonds were also shorter, and there was up to a 30% increase in the number of atomic contacts between the receptor and ligand. This explains the increase in agonist affinity of GPCRs in the active state for a wide range of structurally distinct agonists.

PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling.

G-protein-coupled receptors (GPCRs) are involved in many physiological processes and are therefore key drug targets1. Although detailed structural information is available for GPCRs, the effects of lipids on the receptors, and on downstream coupling of GPCRs to G proteins are largely unknown. Here we use native mass spectrometry to identify endogenous lipids bound to three class A GPCRs. We observed preferential binding of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) over related lipids and confirm that the intracellular surface of the receptors contain hotspots for PtdIns(4,5)P2 binding. Endogenous lipids were also observed bound directly to the trimeric Gαsßγ protein complex of the adenosine A2A receptor (A2AR) in the gas phase. Using engineered Gα subunits (mini-Gαs, mini-Gαi and mini-Gα12)2, we demonstrate that the complex of mini-Gαs with the ß1 adrenergic receptor (ß1AR) is stabilized by the binding of two PtdIns(4,5)P2 molecules. By contrast, PtdIns(4,5)P2 does not stabilize coupling between ß1AR and other Gα subunits (mini-Gαi or mini-Gα12) or a high-affinity nanobody. Other endogenous lipids that bind to these receptors have no effect on coupling, highlighting the specificity of PtdIns(4,5)P2. Calculations of potential of mean force and increased GTP turnover by the activated neurotensin receptor when coupled to trimeric Gαißγ complex in the presence of PtdIns(4,5)P2 provide further evidence for a specific effect of PtdIns(4,5)P2 on coupling. We identify key residues on cognate Gα subunits through which PtdIns(4,5)P2 forms bridging interactions with basic residues on class A GPCRs. These modulating effects of lipids on receptors suggest consequences for understanding function, G-protein selectivity and drug targeting of class A GPCRs.

Insight into partial agonism by observing multiple equilibria for ligand-bound and Gs-mimetic nanobody-bound ß1-adrenergic receptor.

A complex conformational energy landscape determines G-protein-coupled receptor (GPCR) signalling via intracellular binding partners (IBPs), e.g., Gs and ß-arrestin. Using 13C methyl methionine NMR for the ß1-adrenergic receptor, we identify ligand efficacy-dependent equilibria between an inactive and pre-active state and, in complex with Gs-mimetic nanobody, between more and less active ternary complexes. Formation of a basal activity complex through ligand-free nanobody-receptor interaction reveals structural differences on the cytoplasmic receptor side compared to the full agonist-bound nanobody-coupled form, suggesting that ligand-induced variations in G-protein interaction underpin partial agonism. Significant differences in receptor dynamics are observed ranging from rigid nanobody-coupled states to extensive µs-to-ms timescale dynamics when bound to a full agonist. We suggest that the mobility of the full agonist-bound form primes the GPCR to couple to IBPs. On formation of the ternary complex, ligand efficacy determines the quality of the interaction between the rigidified receptor and an IBP and consequently the signalling level.

Structure of the adenosine A(2A) receptor bound to an engineered G protein.

G-protein-coupled receptors (GPCRs) are essential components of the signalling network throughout the body. To understand the molecular mechanism of G-protein-mediated signalling, solved structures of receptors in inactive conformations and in the active conformation coupled to a G protein are necessary. Here we present the structure of the adenosine A(2A) receptor (A(2A)R) bound to an engineered G protein, mini-Gs, at 3.4 Å resolution. Mini-Gs binds to A(2A)R through an extensive interface (1,048 Å2) that is similar, but not identical, to the interface between Gs and the ß2-adrenergic receptor. The transition of the receptor from an agonist-bound active-intermediate state to an active G-protein-bound state is characterized by a 14 Å shift of the cytoplasmic end of transmembrane helix 6 (H6) away from the receptor core, slight changes in the positions of the cytoplasmic ends of H5 and H7 and rotamer changes of the amino acid side chains Arg3.50, Tyr5.58 and Tyr7.53. There are no substantial differences in the extracellular half of the receptor around the ligand binding pocket. The A(2A)R-mini-Gs structure highlights both the diversity and similarity in G-protein coupling to GPCRs and hints at the potential complexity of the molecular basis for G-protein specificity.

Complete Reversible Refolding of a G-Protein Coupled Receptor on a Solid Support.

The factors defining the correct folding and stability of integral membrane proteins are poorly understood. Folding of only a few select membrane proteins has been scrutinised, leaving considerable deficiencies in knowledge for large protein families, such as G protein coupled receptors (GPCRs). Complete reversible folding, which is problematic for any membrane protein, has eluded this dominant receptor family. Moreover, attempts to recover receptors from denatured states are inefficient, yielding at best 40-70% functional protein. We present a method for the reversible unfolding of an archetypal family member, the ß1-adrenergic receptor, and attain 100% recovery of the folded, functional state, in terms of ligand binding, compared to receptor which has not been subject to any unfolding and retains its original, folded structure. We exploit refolding on a solid support, which could avoid unwanted interactions and aggregation that occur in bulk solution. We determine the changes in structure and function upon unfolding and refolding. Additionally, we employ a method that is relatively new to membrane protein folding; pulse proteolysis. Complete refolding of ß1-adrenergic receptor occurs in n-decyl-ß-D-maltoside (DM) micelles from a urea-denatured state, as shown by regain of its original helical structure, ligand binding and protein fluorescence. The successful refolding strategy on a solid support offers a defined method for the controlled refolding and recovery of functional GPCRs and other membrane proteins that suffer from instability and irreversible denaturation once isolated from their native membranes.

Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol-Bound ß1-Adrenergic Receptor.

Comparisons between structures of the ß1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser(5.46), coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. (RS)-4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile (cyanopindolol) is a weak partial agonist of ß1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 4-[(2S)-3-(tert-butylamino)-2-hydroxypropoxy]-7-methyl-1H-indole-2-carbonitrile (7-methylcyanopindolol) would dramatically reduce its efficacy. An eight-step synthesis of 7-methylcyanopindolol was developed and its pharmacology was analyzed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both ß1AR and ß2AR. As predicted, the efficacy of 7-methylcyanopindolol was reduced significantly compared with cyanopindolol, acting as a very weak partial agonist of turkey ß1AR and an inverse agonist of human ß2AR. The structure of 7-methylcyanopindolol-bound ß1AR was determined to 2.4-Å resolution and found to be virtually identical to the structure of cyanopindolol-bound ß1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 Å in 7-methylcyanopindolol-bound ß1AR and the hydroxyl group of Ser(5.46) is positioned 0.8 Å further from the ligand, with respect to the position of the Ser(5.46) side chain in cyanopindolol-bound ß1AR. Thus, the molecular basis for the reduction in efficacy of 7-methylcyanopindolol compared with cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared with antagonists.

To Twitter to Woo: Harnessing the power of social media (SoMe) in nurse education to enhance the student's experience.

This paper explores some of the difficulties, challenges and rewards for student nurses and nurse academics when harnessing social media (SoMe) as part of the overall learning experience. The paper draws upon data in the form of student voices, captured through an online planned Twitter chat. This data analysis provides the basis of a case study on the student experience in practice placements. A planned 1 h Twitter chat took place in June 2013, specifically aimed at student nurses. What transpired was an illuminating debate, eliciting responses from around the globe about learning in practice, mentors, and student support that lasted over 3 h. More importantly, the Twitter chat also included qualified nurses and mentors, listening and responding in real time, offering thoughts and solutions to how support and mentoring could be improved. This was in contrast to how students, locally, currently use a paper based questionnaire to give feedback in isolation. The authenticity of this feedback is often compromised by university link lecturers' who often provide a more sanitised version of this feedback to clinical placement. This paper explores whether it is possible to facilitate a realignment and capture the zeitgeist in order to provide the opportunity for enhancing learning in practice.

Hearing the voices of young people who self-harm: implications for service providers.

The incidence of adolescent self-harm and suicidal behaviour has increased globally, with many adolescents repeating the behaviour. While studies indicate that large numbers of adolescents who self-harm do not seek professional help, research focusing on barriers to help seeking from an adolescent perspective is limited. Locally, a rise in reported and unreported rates of self-harm and a number of suspected child suicides prompted the commissioning of a research project to ascertain young people's experiences of help and support for self-harm and how their future needs could be best met. Qualitative research, adopting an interpretive phenomenological analysis, was used to elicit narratives of adolescents engaging in self-harm. Data were collected via 1:1 interviews with seven participants and analysed in two stages: an analysis of each individual narrative, and thematic analysis across the group. Three themes were identified: (i) cutting out the stress; (ii) stepping onto the path of help; and (iii) cutting to the chase. In conclusion, mental health nurses have a vital role in providing knowledge and support to those likely to have initial contact with this vulnerable group and to the wider population, ensuring we more effectively address the increasing use of this risky behaviour among young people.

The 2.1 Å resolution structure of cyanopindolol-bound ß1-adrenoceptor identifies an intramembrane Na+ ion that stabilises the ligand-free receptor.

The ß1-adrenoceptor (ß1AR) is a G protein-coupled receptor (GPCR) that is activated by the endogenous agonists adrenaline and noradrenaline. We have determined the structure of an ultra-thermostable ß1AR mutant bound to the weak partial agonist cyanopindolol to 2.1 Å resolution. High-quality crystals (100 µm plates) were grown in lipidic cubic phase without the assistance of a T4 lysozyme or BRIL fusion in cytoplasmic loop 3, which is commonly employed for GPCR crystallisation. An intramembrane Na+ ion was identified co-ordinated to Asp872.50, Ser1283.39 and 3 water molecules, which is part of a more extensive network of water molecules in a cavity formed between transmembrane helices 1, 2, 3, 6 and 7. Remarkably, this water network and Na+ ion is highly conserved between ß1AR and the adenosine A2A receptor (rmsd of 0.3 Å), despite an overall rmsd of 2.4 Å for all Cα atoms and only 23% amino acid identity in the transmembrane regions. The affinity of agonist binding and nanobody Nb80 binding to ß1AR is unaffected by Na+ ions, but the stability of the receptor is decreased by 7.5°C in the absence of Na+. Mutation of amino acid side chains that are involved in the co-ordination of either Na+ or water molecules in the network decreases the stability of ß1AR by 5-10°C. The data suggest that the intramembrane Na+ and associated water network stabilise the ligand-free state of ß1AR, but still permits the receptor to form the activated state which involves the collapse of the Na+ binding pocket on agonist binding.

Pain from the inside: understanding the theoretical underpinning of person-centered care delivered by pain teams.

Chronic back pain is globally acknowledged as a common reason why people seek help from health professionals. The complexity of persistent chronic pain can undermine the person's self-esteem and present a number of challenges to an individual's ability to manage their pain. Multi-professional person-centered care is advocated as a key strategy to support people with chronic back pain. However, the impact of these approaches on restoring the person's independence is unclear, and little is known about whether and how person-centered approaches restore autonomy and influence the person's ability to manage their pain. The aim of this grounded theory study was to generate understanding about person-centered care from the perspectives of people with chronic back pain and the multi-professional teams who cared for them. Semi-structured interviews were used to collect data from 17 people with chronic back pain over one year. A constant comparative analytical approach identified five key categories: the skeptical professional, validation, becoming a person, regaining control, and restoring faith. These categories formed the "conditional partnership" as a theory to explain person-centered care, which related to the way in which the partnership developed between the patients and teams. The findings suggest that person-centered care was influenced by the participants' need to be believed and the relationship developed with health care providers. Crucially, these findings suggest that legitimizing the pain experience through person-centered approaches to care can empower people with chronic back pain to regain control of their lives and their pain.

Biophysical fragment screening of the ß1-adrenergic receptor: identification of high affinity arylpiperazine leads using structure-based drug design.

Biophysical fragment screening of a thermostabilized ß1-adrenergic receptor (ß1AR) using surface plasmon resonance (SPR) enabled the identification of moderate affinity, high ligand efficiency (LE) arylpiperazine hits 7 and 8. Subsequent hit to lead follow-up confirmed the activity of the chemotype, and a structure-based design approach using protein-ligand crystal structures of the ß1AR resulted in the identification of several fragments that bound with higher affinity, including indole 19 and quinoline 20. In the first example of GPCR crystallography with ligands derived from fragment screening, structures of the stabilized ß1AR complexed with 19 and 20 were determined at resolutions of 2.8 and 2.7 Å, respectively.

The importance of interactions with helix 5 in determining the efficacy of ß-adrenoceptor ligands.

Structures of the inactive state of the thermostabilized ß1-adrenoceptor have been determined bound to eight different ligands, including full agonists, partial agonists, inverse agonists and biased agonists. Comparison of the structures shows distinct differences within the binding pocket that correlate with the pharmacological properties of the ligands. These data suggest that full agonists stabilize a structure with a contracted binding pocket and a rotamer change of serine (5.46) compared with when antagonists are bound. Inverse agonists may prevent both of these occurrences, whereas partial agonists stabilize a contraction of the binding pocket but not the rotamer change of serine (5.46). It is likely that subtle changes in the interactions between transmembrane helix 5 (H5) and H3/H4 on agonist binding promote the formation of the activated state.

'That was helpful no one has talked to me about that before': Research participation as a therapeutic activity.

There is considerable interest in the various ethical problems associated with undertaking health and social science research. Participants in such research are often considered vulnerable because of their health status, social position, or dependence on others for health and welfare services. Researchers and ethics committees pay scrupulous attention to the identification and amelioration of risks to participants. Rarely are the benefits to participants of engaging in research highlighted or drawn to the attention of potential participants. Such potential benefits need to be considered by researchers and reviewers when considering the balance of benefits and harms associated with research projects. In this paper, we particularly consider the psychotherapeutic benefits of participation in research.

Students' experiences of cooperation with nurse teacher during their clinical placements: an empirical study in a Western European context.

In many European countries during the last decade, the clinical role of the nurse teacher has changed from a clinical skilled practitioner to a liaison person working between educational and health care provider organisations. This study explored pre-registration nursing students' perceptions of cooperation with nurse teachers during their clinical placements in nine Western European countries. The study also assessed the type and range of e-communication between students and nurse teachers and whom the students' perceived as their most important professional role model. The study is a descriptive survey. Quantitative data were collected from 17 higher education institutes of nursing located in the northern, middle and southern parts of Europe. The purposive sample (N = 1903) comprised students who had participated in courses which included clinical placements. The data were analysed using descriptive statistics. Comparisons between the groups were made using cross-tabulation. The majority (57%) of students met their nurse teacher 1-3 times during their placement while 13% of the students did not meet their nurse teacher at all. Additionally, 66% of respondents used some form of e-communication (e-mail, mobile text messages etc.) to communicate with their nurse teacher. It is important to clarify the division of labour between nurse teachers and Mentors. There are both opportunities and challenges in how to utilise information technology to more effectively promote cooperation between students and nurse teachers.