Providing care to marginalised communities: a qualitative study of community pharmacy teams.

BACKGROUND: Health inequalities in the UK are widening, particularly since the COVID-19 pandemic. Community pharmacies are the most visited healthcare provider in England and are ideally placed to provide and facilitate access to care for those most disadvantaged. AIM: To explore the experiences and needs of community pharmacy teams in providing care for marginalised groups and how this has changed since the COVID-19 pandemic. DESIGN AND SETTING: A qualitative study in community pharmacy and across primary care. METHOD: Semi-structured interviews were undertaken with members of community pharmacy teams, primary care network (PCN) pharmacists, GPs, and nurses in the North of England. RESULTS: In total, 31 individuals participated in an interview (26 pharmacy staff, three GPs, and two nurses). Most participants acknowledged that their pharmacy had become busier since COVID-19 because of increased footfall compounded by patient difficulties in navigating remote digital systems. Few participants had received any formal training on working with marginalised communities; however, organisational barriers (such as lack of access to translation facilities) combined with interorganisational barriers (such as lack of integrated care) made it more difficult to provide care for some marginalised groups. Despite this, the continuity of care provided by many pharmacies was viewed as an important factor in enabling marginalised groups to access and receive care. CONCLUSION: There are opportunities to better utilise the skills of community pharmacy teams. Resources, such as access to translation services, and interventions to enable better communication between community pharmacy teams and other primary care services, such as general practice, are essential.

Young adult male LEW.1WR1 rats have reduced beta cell area and develop glucose intolerance.

Prediabetes affects 1 in 3 American adults and is characterized by insulin resistance, insulin hypersecretion, and impaired glucose tolerance. Weanling LEW.1WR1 (1WR1) rats have increased blood insulin concentrations, so we hypothesized that young adult 1WR1 rats would develop impaired glucose tolerance due to the poor regulation of insulin. We monitored glucose tolerance, insulin tolerance, and weight gain for 10 weeks to assess if there was a decline in glucose processing over time. 1WR1 rats were significantly more glucose intolerant after 8 weeks. 1WR1 rats had increased body mass, yet abdominal fat mass was not significantly increased. Although the 1WR1 rats had increased circulating insulin and glucagon protein levels, 1WR1 rat beta cell area was significantly reduced. There may be underlying insulin resistance as evidenced by dysfunctional insulin regulation during fasting. Understanding the metabolic phenotype of this rat model can provide insight into the human pathophysiological changes that increase susceptibility to glucose intolerance and prediabetes.

Approaches used to enhance transition and retention for newly qualified nurses (NQNS): A rapid evidence assessment.

AIM: To undertake a rapid evidence assessment of approaches used to enhance nurse transition and retention for newly qualified nurses and to evaluate the strength of the evidence for specific approaches to nurse transition and retention. DESIGN: A rapid evidence assessment was undertaken. Electronic databases were searched, and the full texts of relevant papers were retrieved. Studies were appraised using relevant Critical Appraisal Skills Programme and Mixed Methods Assessment Tools and a single descriptor of quality: high; medium; or low was assigned to each output. Given the disparity in methods, the lack of randomised trials, results could not be combined; therefore, a descriptive approach was used to synthesise and present the data. DATA SOURCES: The search was undertaken using: specific database searching; and secondary searching of relevant websites. Electronic databases (CINAHL complete, Academic search premier, Open Grey, ERIC* (Education), Web of Science-Social Science Citation Index and PubMed) were searched during February 2018. RESULTS: Orientation and creating supportive environments were frequently reported as being effective in enhancing transition across a range of studies. A range of methods: quasi-experimental, survey and qualitative were used. Generally, the quality of most studies was poor. CONCLUSIONS: Despite decades of research into the experiences of newly qualified nurses and development of schemes and frameworks to support them during this period, there is little substantive or robust evidence in terms of impact on retention. Further research into the longer-term retention of newly qualified nurses is recommended. Longitudinal studies would be beneficial in assessing the efficacy of approaches to enhancing retention.

Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR).

OBJECTIVE: To investigate the effectiveness of combining mirtazapine with serotonin-noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants for treatment resistant depression in primary care. DESIGN: Two parallel group multicentre phase III randomised placebo controlled trial. SETTING: 106 general practices in four UK sites; Bristol, Exeter, Hull, and Keele/North Staffs, August 2013 to October 2015. PARTICIPANTS: 480 adults aged 18 or more years who scored 14 or more on the Beck depression inventory, second revision, fulfilled ICD-10 (international classification of diseases, 10th revision) criteria for depression, and had used an SSRI or SNRI for at least six weeks but were still depressed. 241 were randomised to mirtazapine and 239 to placebo, both given in addition to usual SSRI or SNRI treatment. Participants were stratified by centre and minimised by baseline Beck depression inventory score, sex, and current psychological therapy. They were followed up at 12, 24, and 52 weeks. 431 (89.8%) were included in the (primary) 12 week follow-up. MAIN OUTCOME MEASURES: Depressive symptoms at 12 weeks after randomisation, measured using the Beck depression inventory II score as a continuous variable. Secondary outcomes included measures of anxiety, quality of life, and adverse effects at 12, 24, and 52 weeks. RESULTS: Beck depression inventory II scores at 12 weeks were lower in the mirtazapine group after adjustment for baseline scores and minimisation or stratification variables, although the confidence interval included the null (mean (SD) scores at 12 weeks: 18.0 (12.3) in the mirtazapine group, 19.7 (12.4) in the placebo group; adjusted difference between means -1.83 (95% confidence interval -3.92 to 0.27); P=0.09). Adverse effects were more common in the mirtazapine group and were associated with the participants stopping the trial drug. CONCLUSION: This study did not find evidence of a clinically important benefit for mirtazapine in addition to an SSRI or SNRI over placebo in a treatment resistant group of primary care patients with depression. This remains an area of important unmet need where evidence of effective treatment options is limited. TRIAL REGISTRATION: Current Controlled Trials ISRCTN06653773.

Profile of ethnicity, living arrangements and loneliness amongst older adults in Aotearoa New Zealand: A national cross-sectional study.

OBJECTIVE: To explore the patterns of living arrangements, ethnicity and loneliness amongst older adults (aged 65+ years) living at home. METHODS: National interRAI-HC (International Residential Assessment Instrument-Home Care) assessments conducted between 1 September 2012 and 31 January 2016 were analysed. Analysis focused on the associations between loneliness and both ethnic groups and living arrangements. RESULTS: There were 71 859 eligible participants, with average age 82.7 years, comprising Maori (5%), Pasifika (3%), Asian (2%) and European/Other (89%) ethnic identification. Most stated that they were not lonely (79%), but those living alone were more likely to be lonely (29%) than those living with others (14%) (P < 0.05). Amongst those living alone, significant differences in the likelihood of being lonely emerged between ethnic groups (P < 0.05). CONCLUSIONS: Ethnic identification and living arrangements were significantly associated with the likelihood of loneliness for those having an interRAI-HC assessment. Efforts to reduce the negative impacts of loneliness need a nuanced approach.

Working memory impairment in calcineurin knock-out mice is associated with alterations in synaptic vesicle cycling and disruption of high-frequency synaptic and network activity in prefrontal cortex.

Working memory is an essential component of higher cognitive function, and its impairment is a core symptom of multiple CNS disorders, including schizophrenia. Neuronal mechanisms supporting working memory under normal conditions have been described and include persistent, high-frequency activity of prefrontal cortical neurons. However, little is known about the molecular and cellular basis of working memory dysfunction in the context of neuropsychiatric disorders. To elucidate synaptic and neuronal mechanisms of working memory dysfunction, we have performed a comprehensive analysis of a mouse model of schizophrenia, the forebrain-specific calcineurin knock-out mouse. Biochemical analyses of cortical tissue from these mice revealed a pronounced hyperphosphorylation of synaptic vesicle cycling proteins known to be necessary for high-frequency synaptic transmission. Examination of the synaptic vesicle cycle in calcineurin-deficient neurons demonstrated an impairment of vesicle release enhancement during periods of intense stimulation. Moreover, brain slice and in vivo electrophysiological analyses showed that loss of calcineurin leads to a gene dose-dependent disruption of high-frequency synaptic transmission and network activity in the PFC, correlating with selective working memory impairment. Finally, we showed that levels of dynamin I, a key presynaptic protein and calcineurin substrate, are significantly reduced in prefrontal cortical samples from schizophrenia patients, extending the disease relevance of our findings. Our data provide support for a model in which impaired synaptic vesicle cycling represents a critical node for disease pathologies underlying the cognitive deficits in schizophrenia.

A novel non-CB1/TRPV1 endocannabinoid-mediated mechanism depresses excitatory synapses on hippocampal CA1 interneurons.

Endocannabinoids (eCBs) mediate various forms of synaptic plasticity at excitatory and inhibitory synapses in the brain. The eCB anandamide binds to several receptors including the transient receptor potential vanilloid 1 (TRPV1) and cannabinoid receptor 1 (CB1). We recently identified that TRPV1 is required for long-term depression at excitatory synapses on CA1 hippocampal stratum radiatum interneurons. Here we performed whole-cell patch clamp recordings from CA1 stratum radiatum interneurons in rat brain slices to investigate the effect of the eCB anandamide on excitatory synapses as well as the involvement of Group I metabotropic glutamate receptors (mGluRs), which have been reported to produce eCBs endogenously. Application of the nonhydrolysable anandamide analog R-methanandamide depressed excitatory transmission to CA1 stratum radiatum interneurons by ∼50%. The Group I mGluR agonist DHPG also depressed excitatory glutamatergic transmission onto interneurons to a similar degree, and this depression was blocked by the mGluR5 antagonist MPEP (10 µM) but not by the mGluR1 antagonist CPCCOEt (50 µM). Interestingly, however, neither DHPG-mediated nor R-methanandamide-mediated depression was blocked by the TRPV1 antagonist capsazepine (10 µM), the CB1 antagonist AM-251 (2 µM) or a combination of both, suggesting the presence of a novel eCB receptor or anandamide target at excitatory hippocampal synapses. DHPG also occluded R-methanandamide depression, suggesting the possibility that the two drugs elicit synaptic depression via a shared signaling mechanism. Collectively, this study illustrates a novel CB1/TRPV1-independent eCB pathway present in the hippocampus that mediates depression at excitatory synapses on CA1 stratum radiatum interneurons.

Clorgyline-mediated reversal of neurological deficits in a Complexin 2 knockout mouse.

Complexin 2 is a protein modulator of neurotransmitter release that is downregulated in humans suffering from depression, animal models of depression and neurological disorders such as Huntington's disease in which depression is a major symptom. Although complexin 2 knockout (Cplx2-/-) mice are overtly normal, they show significant abnormalities in cognitive function and synaptic plasticity. Here we show that Cplx2-/- mice also have disturbances in emotional behaviours that include abnormal social interactions and depressive-like behaviour. Since neurotransmitter deficiencies are thought to underlie depression, we examined neurotransmitter levels in Cplx2-/- mice and found a significant decrease in levels of noradrenaline and the serotonin metabolite 5-hydroxyindoleacetic acid in the hippocampus. Chronic treatment with clorgyline, an irreversible inhibitor of monoamine oxidase A, restored hippocampal noradrenaline to normal levels (from 60 to 97% of vehicle-treated Cplx2+/+ mice, P<0.001), and reversed the behavioural deficits seen in Cplx2-/- mice. For example, clorgyline-treated Cplx2-/- mice spent significantly more time interacting with a novel visitor mouse compared with vehicle-treated Cplx2-/- mice in the social recognition test (34 compared with 13%, P<0.01). We were also able to reverse the selective deficit seen in mossy fibre-long-term potentiation (MF-LTP) in Cplx2-/- mice using the noradrenergic agonist isoprenaline. Pre-treatment with isoprenaline in vitro increased MF-LTP by 125% (P<0.001), thus restoring it to control levels. Our data strongly support the idea that complexin 2 is a key player in normal neurological function, and that downregulation of complexin 2 could lead to changes in neurotransmitter release sufficient to cause significant behavioural abnormalities such as depression.

Looking ahead: the use of prospective analysis to improve the quality and safety of care.

Patient safety and quality are paramount at Lakeridge Health, in Durham, Ontario. The use of prospective analysis has provided us with the opportunity to understand systemic issues in a hospital organization and, as such, to implement sustainable changes that are meaningful to staff and will ensure an enhanced patient experience. To complement Accreditation Canada required organizational practices and a commitment to continuous quality improvement, Lakeridge Health has recognized how an inter-professional approach, staff engagement and use of quality tools support the focus on quality and safety. The implementation of best practices (both clinical and administrative processes) has been possible as a direct result of using this approach. This article outlines three case studies representing different applications of the prospective analysis methodology: ensuring safety with endoscopy processes, minimizing risk in narcotic administration and enhancing infection control practices. In each case, the methodology of prospective analysis was used to ensure the implementation of sustainable change that spans all sites in a multi-sited health facility. This article also includes lessons learned in an effort to understand and implement this quality methodology in healthcare.

Hot flash: TRPV channels in the brain.

TRPV1 (transient receptor potential, vanilloid) channels belong to a family of ligand-gated ion channels gated not only by the binding of certain lipophilic molecules but also by extracellular protons and physical stimuli such as heat or osmotic pressure changes. These nonselective cation channels are permeable to Na(+) and K(+) and are also very Ca(2+) permeable; in fact, TRPV1 is as Ca(2+) permeable as the NMDA receptor channel and can, thus, act as a trigger for Ca(2+)-mediated cell signaling. Although these channels are highly expressed in primary sensory afferents, accumulating evidence indicates that TRPV family channels are also present in the brain. Here, we review evidence that TRPV channels in the central nervous system might contribute to many basic neuronal functions including resting membrane potential, neurotransmitter release and synaptic plasticity.

A longitudinal study of stress and psychological distress in nurses and nursing students.

AIM: The aim of this study was to investigate how differences in life events and stress contribute to psychological distress in nurses and nursing students. BACKGROUND: Stress is an issue for nursing students and qualified nurses leading to psychological distress and attrition. DESIGN: A longitudinal study using four time waves was conducted between 1994-1997. METHODS: Measures were taken of stress, life events and psychological distress in addition to a range of demographic data. Data were analysed using descriptive statistics, linear modelling and mixed-effects modelling. The study was set in Scotland, UK and used newly qualified nurses and nursing students from four university departments of nursing over four years. The study was initiated with 359 participants (147 nurses and 212 nursing students) and complete data were obtained for 192 participants. RESULTS: Stress levels, psychological distress and life events are all associated within time and across time. At baseline, life events and stress contributed significantly to psychological distress. The pattern of psychological distress differed between the nursing students and the newly qualified nurses with a high level in the nurses after qualifying and starting their career. CONCLUSION: Stress, individual traits, adverse life events and psychological distress are all interrelated. Future lines of enquiry should focus on the transition between being a nursing student and becoming a nurse. RELEVANCE TO CLINICAL PRACTICE: Stress and psychological distress may have negative outcomes for the retention of nursing students in programmes of study and newly qualified nurses in the nursing workforce.

"A wealth of knowledge": A survey of the employment experiences of older nurses and midwives in the NHS.

BACKGROUND: The United Kingdom's National Health Service workforce is ageing, and the specific needs of this sector of its workforce need to be addressed. Nursing and midwifery shortage is a worldwide issue, and with increasing demands for care the retention of older nurses and midwives is crucial. OBJECTIVES: To report on the employment experiences of nurses and midwives with a particular focus on issues relating to age, ethnicity, ill-health and disability. DESIGN: The postal survey was developed following a literature review and analysis of National Health Service and Government policy documents. SETTINGS: This was a UK-wide survey of nurses and midwives working in National Health Service Trusts and Primary Care Trusts. PARTICIPANTS/METHODS: A postal survey of nurses and midwives was undertaken between May and December 2005. National Health Service Trusts and Primary Care Trusts (n=44) identified as having policies relevant to the study were contacted regarding the procedure for seeking research governance approval. Thirteen National Health Service Trusts and Primary Care Trusts participated, with 2610 surveys distributed; 510 surveys were returned (20% response rate). RESULTS: Nurses and midwives aged 50 years and over had undertaken fewer Continuing Professional Development activities than nurses and midwives under 50. Whilst not related to age, the study also found that 20% of the survey sample reported experiencing some form of discrimination. Nurses and midwives did not differ on either quality of life or psychological health using standard instruments. Having a disability did not lead to greater psychological morbidity but did have a negative effect on quality of life. Having a work-related illness had a negative impact on both quality of life and psychological morbidity. In relation to ethnicity, black nurses and midwives reported lower psychological morbidity than other ethnic groups; that is, they enjoyed a higher level of mental well-being. CONCLUSION: The nursing and midwifery workforce is ageing worldwide with a significant proportion now approaching, or having already reached, potential retirement age. With the recent introduction of the age legislation the working lives of older nurses and midwives in the National Health Service have never been more relevant. Whilst access to Continuing Professional Development is pertinent to the retention of nurses and midwives of all ages, in this study, older nurses reported less access than younger nurses.

TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons.

TRPV1 receptors have classically been defined as heat-sensitive, ligand-gated, nonselective cation channels that integrate nociceptive stimuli in sensory neurons. TRPV1 receptors have also been identified in the brain, but their physiological role is poorly understood. Here we report that TRPV1 channel activation is necessary and sufficient to trigger long-term synaptic depression (LTD). Excitatory synapses onto hippocampal interneurons were depressed by either capsaicin, a potent TRPV1 channel activator, or the endogenously released eicosanoid, 12-(S)-HPETE, whereas neighboring excitatory synapses onto CA1 pyramidal cells were unaffected. TRPV1 receptor antagonists also prevented interneuron LTD. In brain slices from TRPV1-/- mice, LTD was absent, and neither capsaicin nor 12-(S)-HPETE elicited synaptic depression. Our results suggest that, in the hippocampus, TRPV1 receptor activation selectively modifies synapses onto interneurons. Like other forms of hippocampal synaptic plasticity, TRPV1-mediated LTD may have a role in long-term changes in physiological and pathological circuit behavior during learning and epileptic activity.

Structural and functional studies on DHC, the diheme cytochrome c from Rhodobacter sphaeroides, and its interaction with SHP, the sphaeroides heme protein.

The diheme cytochrome c (DHC) from Rhodobacter sphaeroides is a soluble protein with a mass of 16 kDa that represents a new class of c-type cytochrome [Vandenberghe, I., et al. (1998) Biochemistry 37, 13075-13081]. The gene encoding DHC is associated with another encoding a cytochrome known as SHP (sphaeroides heme protein). It is believed that DHC is the electron donor for SHP, which is known to bind oxygen. To gain further insight into the properties and role of DHC, we have carried out structure-function studies on the protein and examined its interaction with SHP. The crystal structures of native and recombinant DHC have been determined to resolutions of 1.85 and 2.0 A, respectively. The structures show that DHC folds into two distinct domains each containing one heme. While the N-terminal domain is a class I cytochrome c, the C-terminal domain shows no similarity to any existing structures and thus constitutes a novel cytochrome c structural motif. The shortest, edge-to-edge, distance between the heme groups is 10.2 A, and this distance is bridged by Tyr31, thus ensuring fast internal electron transfer. DHC binds strongly to its proposed physiological partner, SHP (K(d) = 0.26 microM in 10 mM HEPES at pH 7.2 and 25 degrees C). However, at higher salt concentrations, the binding becomes much weaker, indicating the importance of electrostatic interactions. DHC is also very efficient in electron transfer to SHP with a second-order rate constant of 1.8 x 10(7) M(-)(1) s(-)(1) (at pH 7.2, 10 degrees C, and I = 500 mM). The reduction potentials of DHC and SHP are also suitably ordered for a favorable reaction with the hemes of DHC showing potentials of -310 and -240 mV, respectively, and that for SHP being -105 mV. These potentials are unaltered upon complex formation.

A similar impairment in CA3 mossy fibre LTP in the R6/2 mouse model of Huntington's disease and in the complexin II knockout mouse.

Complexin II is reduced in Huntington's disease (HD) patients and in the R6/2 mouse model of HD. Mice lacking complexin II (Cplx2-/- mice) show selective cognitive deficits that reflect those seen in R6/2 mice. To determine whether or not there is a common mechanism that might underlie the cognitive deficits, long-term potentiation (LTP) was examined in the CA3 region of hippocampal slices from R6/2 mice and Cplx2-/- mice. While associational/commissural (A/C) LTP was not significantly different, mossy fibre (MF) LTP was significantly reduced in slices from R6/2 mice and Cplx2-/- mice compared with wild-type (WT) and Cplx2+/+ control mice. MF field excitatory postsynaptic potentials (fEPSPs) in response to paired stimuli were not significantly different between control mice and R6/2 or Cplx2-/- mice, suggesting that MF basal glutamate release is unaffected. Forskolin (30 microm) caused an increase in glutamate release at MF synapses in slices from R6/2 mice and from Cplx2-/- mice that was not significantly different from that seen in control mice, indicating that the capacity for increased glutamate release is not diminished. Thus, R6/2 mice and Cplx2-/- mice have a common selective impairment of MF LTP in the CA3 region. Together, these data suggest that complexin II is required for MF LTP, and that depletion of complexin II causes a selective impairment in MF LTP in the CA3 region. This impairment in MF LTP could contribute to spatial learning deficits observed in R6/2 and Cplx2-/- mice.

Characterization of nociceptin/orphanin FQ binding sites in dog brain membranes.

Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ receptor (NOP), whose characteristics in the dog are unknown. We therefore compared [(3)H]N/OFQ binding in dog and rat brain membranes. Radioligand saturation/competition studies with these membranes and leucyl-[(3)H]N/OFQ(1-17)OH or the novel radioligand [(3)H]N/OFQ(1-13)NH(2) were performed to determine receptor density and ligand affinity. The density of classic opioid receptors was determined by using [(3)H]diprenorphine. Leucyl-[(3)H]N/OFQ(1-17)OH binding was concentration dependent and saturable in dog (maximum binding capacity [B(max)], 28.7 +/- 2.8 fmol/mg of protein; equilibrium dissociation constant as negative log [pK(d)], 10.27 +/- 0.11) and rat (B(max), 137.0 +/- 12.9 fmol/mg of protein; pK(d), 10.41 +/- 0.05). In comparison, the B(max) and pK(d) of [(3)H]diprenorphine were, respectively, 77.7 +/- 5.3 fmol/mg of protein and 9.74 +/- 0.09 in dog and 79.1 +/- 18.2 fmol/mg of protein and 9.51 +/- 0.04 in rat. In dog, [(3)H]N/OFQ(1-13)NH(2) binding to NOP receptors was also saturable (B(max), 23.7 +/- 2.0 fmol/mg of protein; pK(d), 10.16 +/- 0.12). In both species, leucyl-[(3)H]N/OFQ(1-17)OH was displaced by various NOP ligands. Dynorphin A, N/OFQ(1-5)NH(2), and nocistatin were essentially inactive. There was a significant positive correlation (r(2) = 0.95; P < 0.0001) between pK(i) values (an estimate of affinity) obtained in displacement studies in rat and dog. We have demonstrated a low density of NOP receptors, measured with two radioligands, in dog, and these receptors display a high degree of pharmacological similarity with those natively expressed in the rat.