Development of an intervention to manage benzodiazepine dependence and high-risk use in the context of escalating drug related deaths in Scotland: an application of the MRC framework.

BACKGROUND: Scotland has the highest rate of drug related deaths (DRD) in Europe. These are deaths in people who use drugs such as heroin, cocaine, benzodiazepines and gabapentinoids. It is a feature of deaths in Scotland that people use combinations of drugs which increases the chance of a DRD. Many deaths involve 'street' benzodiazepines, especially a drug called etizolam. Many of the 'street' benzodiazepines are not licensed in the UK so come from illegal sources. People who use opiates can be prescribed a safer replacement medication (e.g., methadone). While guidance on management of benzodiazepines use highlights that there is little evidence to support replacement prescribing, practice and evidence are emerging. AIM: To develop an intervention to address 'street' benzodiazepines use in people who also use opiates. METHODS: The MRC Framework for Complex Interventions was used to inform research design. Co-production of the intervention was achieved through three online workshops with clinicians, academics working in the area of substance use, and people with lived experience (PWLE). Each workshop was followed by a PWLE group meeting. Outputs from workshops were discussed and refined by the PWLE group and then further explored at the next workshop. RESULTS: After these six sessions, a finalised logic model for the intervention was successfully achieved that was acceptable to clinicians and PWLE. Key components of the intervention were: prescribing of diazepam; anxiety management, sleep, and pain; and harm reduction resources (locked box and a range of tips), personal safety conversations, as well as a virtual learning environment. CONCLUSION: A co-produced intervention was developed for next stage clinical feasibility testing.

A quality improvement project for delirium prevention and management over the Greater Manchester Critical Care Network.

BACKGROUND: Delirium is a common complication of critical illness with a significant impact on patient morbidity and mortality. The Greater Manchester Critical Care Network established the Delirium Reduction Working Group in 2015. This article describes a region-wide delirium improvement project launched by that group. METHODS: Multiple Plan-Do-Study-Act cycles were undertaken. Cycle 1: April 2015 demonstrated only 48% of patients had a formal delirium screen. Following this a network-wide event took place and the Delirium Standards for the Greater Manchester Critical Care Network were produced. Cycle 2: May 2016 quarterly audits across the network monitored compliance against the agreed standards. Group events involved implementation of a delirium care bundle, sharing best practice, educating staff and providing guidance on the management of delirium. Cycle 3: November 2016 quarterly audit continued and a regional delirium study day was rolled out across the region. RESULTS: We have 14 different units across our network, all of which have participated in the audit. The first audit showed a delirium point prevalence of 28%, subsequent point prevalence audits demonstrated rates as low as 13%. There has also been an improvement in the use of delirium screening tools. In the first audit 37% of patients had two delirium screens in 24 h, this has increased to 60% in the latest audit. Improvements were also made in availability of sensory aids and pain assessments. CONCLUSION: The project has demonstrated the feasibility of delivering a coordinated delirium improvement project across multiple critical care units.

Implementing pelvic floor muscle training for women with pelvic organ prolapse: a realist evaluation of different delivery models.

BACKGROUND: Pelvic Floor Muscle Training (PFMT) has been shown to be effective for pelvic organ prolapse in women, but its implementation in routine practice is challenging due to lack of adequate specialist staff. It is important to know if PFMT can be delivered by different staff skill mixes, what barriers and facilitators operate in different contexts, what strategies enable successful implementation and what are the underlying mechanisms of their action. PROPEL intervention was designed to maximise the delivery of effective PFMT in the UK NHS using different staff skill mixes. We conducted a realist evaluation (RE) of this implementation to understand what works, for whom, in what circumstances and why. METHODS: Informed by the Realist and RE-AIM frameworks, the study used a longitudinal, qualitative, multiple case study design. The study took place in five, purposively selected, diverse NHS sites across the UK and proceeded in three phases to identify, test and refine a theory of change. Data collection took place at 4 time points over an 18 month implementation period using focus groups and semi-structured interviews with a range of stakeholders including service leads/managers, senior practitioners, newly trained staff and women receiving care in the new service models. Data were analysed using thematic framework approach adapted to identify Context, Mechanism and Outcome (CMO) configurations of the RE. RESULTS: A heightened awareness of the service need among staff and management was a mechanism for change, particularly in areas where there was a shortage of skilled staff. In contrast, the most established specialist physiotherapist-delivered PFMT service activated feelings of role protection and compromised quality, which restricted the reach of PFMT through alternative models. Staff with some level of prior knowledge in women's health and adequate organisational support were more comfortable and confident in new role. Implementation was seamless when PFMT delivery was incorporated in newly trained staff's role and core work. CONCLUSION: Roll-out of PFMT delivery through different staff skill mixes is possible when it is undertaken by clinicians with an interest in women's health, and carefully implemented ensuring adequate levels of training and ongoing support from specialists, multi-disciplinary teams and management.

Attitudes to lesbian, gay, bisexual and transgender parents seeking health care for their children in two early parenting services in Australia.

AIMS AND OBJECTIVES: To examine the attitudes to and knowledge and beliefs about homosexuality of nurses and allied professionals in two early parenting services in Australia. BACKGROUND: Early parenting services employ nurses and allied professionals. Access and inclusion policies are important in community health and early childhood service settings. However, little is known about the perceptions of professionals who work within early parenting services in relation to lesbian, gay, bisexual and transgender families. DESIGN: This is the final in a series of studies and was undertaken in two early parenting services in two states in Australia using a cross-sectional design with quantitative and qualitative approaches. METHODS: Validated questionnaires were completed by 51 nurses and allied professionals and tested with chi-squared test of independence (or Fisher's exact test), Mann-Whitney U-test, Kruskal-Wallis one-way analysis of variance or Spearman's rank correlation. Thematic analysis examined qualitative data collected in a box for free comments. RESULTS: Of the constructs measured by the questionnaires, no significant relationships were found in knowledge, attitude and gay affirmative practice scores by sociodemographic variables or professional group. However, attitude scores towards lesbians and gay men were significantly negatively affected by conservative political affiliation (p = 0·038), held religious beliefs (p = 0·011) and frequency of praying (p = 0·018). Six overall themes were found as follows: respect, parenting role, implications for the child, management, disclosure, resources and training. CONCLUSIONS: The study provided an in-depth analysis of the attitudes, knowledge and beliefs of professionals in two early parenting services, showing that work is needed to promote acceptance of diversity and the inclusion of lesbian, gay, bisexual and transgender families in planning, developing, evaluating and accessing early parenting services. RELEVANCE TO CLINICAL PRACTICE: Access and inclusion plans for lesbian, gay, bisexual and transgender families are crucial in early parenting services in Australia and should be included in professional development programmes.

Extended parenting education in an early parenting centre: A mixed-methods study.

This article reports findings from a process and impact study of a residential early parenting centre programme in Australia. The programme supports parents with young children under the age of three, referred from health and child protection services. Multiple sources of data were used from interviews, focus groups, direct observations, observer notes and a parenting sense of competence questionnaire. Qualitative data were analysed using thematic analyses, and paired t-tests were used to test data from the questionnaire. Three themes emerged from thematic analysis of the qualitative data: engaging families, building parenting capacity and transitioning back to the community. Parents' perceptions of parent competence improved significantly between admission and discharge for participating families. Detailed accounts of the way in which nurses work to achieve positive outcomes in relation to parenting confidence and satisfaction in the short term have provided useful insights into often taken-for-granted support processes in working with referred parents. The complexity of the nurses' role and implications for nursing practice in residential parenting centres are discussed. Future research is warranted to determine longer-term benefits of this programme being delivered in a residential early parenting centre.

A collaborative approach to perinatal and infant mental health service delivery in Australia.

OBJECTIVE: The objective of this paper is to report on the development and implementation of a community-based perinatal and infant mental health day program for mothers with psychiatric illness. The program was initiated through interagency collaboration between adult mental health, infant mental health and community child health services in Queensland, Australia in response to calls for an integrated approach that could be delivered state-wide if successful. Preliminary results of the program's evaluation are provided. METHOD: A pre-post survey design was used to assess the influence the program had on maternal mental and emotional well-being and the maternal-infant relationship. Twenty-one women receiving treatment for perinatal mental illness gave consent to attend the 6-week day program integrating three currently separate and discrete services: adult mental health, infant mental health and community child health. RESULTS: Clinically and statistically significant improvements were observed for maternal mental health, and parent-infant relationships following the program. CONCLUSIONS: These findings support interagency collaboration between adult mental health, infant mental health and community child health services to deliver services to women with mental illness with newborns and their families. The utility of using a collaborative approach in a community setting endorses more comprehensive and longer-term evaluation of effectiveness and cost benefit.

A novel series of IKKß inhibitors part II: description of a potent and pharmacologically active series of analogs.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.

A novel series of IKKß inhibitors part I: Initial SAR studies of a HTS hit.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.

An inhibitory metabolite leads to dose- and time-dependent pharmacokinetics of (R)-N-{1-[3-(4-ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxy-phenyl)-acetamide (AMG 487) in human subjects after multiple dosing.

(R)-N-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]-pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxyphenyl)-acetamide (AMG 487) is a potent and selective orally bioavailable chemokine (C-X-C motif) receptor 3 (CXCR3) antagonist that displays dose- and time-dependent pharmacokinetics in human subjects after multiple oral dosing. Although AMG 487 exhibited linear pharmacokinetics on both days 1 and 7 at the 25-mg dose, dose- and time-dependent kinetics were evident at the two higher doses. Nonlinear kinetics were more pronounced after multiple dosing. Area under the plasma concentration-time curve from 0 to 24 h [AUC((0-24 h))] increased 96-fold with a 10-fold increase in dose on day 7 compared with a 28-fold increase in AUC((0-24 h)) on day 1. These changes were correlated with time- and dose-dependent decreases in the metabolite to parent plasma concentrations, suggesting that these changes result from a decrease in the oral clearance (CL) of AMG 487 (e.g., intestinal/hepatic first-pass metabolism and systemic CL). The biotransformation of AMG 487 is dependent on CYP3A and results in the formation of two primary metabolites, a pyridyl N-oxide AMG 487 (M1) and an O-deethylated AMG 487 (M2). One of these metabolites, M2, undergoes further metabolism by CYP3A. M2 has also been demonstrated to inhibit CYP3A in a competitive (K(i)=0.75 microM) manner as well as via mechanism-based inhibition (unbound K(I)=1.4 microM, k(inact)=0.041 min(-1)). Data from this study implicate M2-mediated CYP3A mechanism-based inhibition as the proximal cause for the time-dependent pharmacokinetics of AMG 487. However, the sequential metabolism of M2, nonlinear AMG 487 pharmacokinetics, and the inability to accurately determine the role of intestinal AMG 487 metabolism complicates the correlation between M2 plasma concentrations and the time-dependent AMG 487 pharmacokinetic changes.

Smaller aortic dimensions do not fully account for the greater pulse pressure in elderly female hypertensives.

This study examined the importance of aortic dimensions in determining pulse pressure in elderly hypertensives participating in the 2nd Australian National Blood Pressure Study, including a substantial number not previously receiving blood pressure lowering medication. Aortic dimensions were determined by ultrasound at the transverse arch and at the insertion of the aortic valve. Unadjusted data showed negative (P<0.001) correlations between central (carotid) and (brachial) peripheral pulse pressure and both arch (-0.200, -0.181) and outflow tract (-0.238, -0.238) diameters. Correlations were similar in those previously treated with blood pressure lowering medication and in the treatment naïve. Central pulse pressure (84+/-26 versus 75+/-28 mm Hg, P<0.001) was higher and aortic dimensions (transverse arch 2.56+/-0.31 versus 2.88+/-0.35 mm, P<0.001) smaller in women than men. Women had greater aortic stiffness (beta index 29.4+/-36.1 versus 22.1+/-21.3, P<0.03). Other bivariate correlates of central pulse pressure were age, mean arterial pressure, height, heart rate, augmentation index, aortic stiffness (all P<0.001), and weight (P=0.027). In multivariate analyses gender remained a predictor of central pulse pressure (P<0.001) even with inclusion of aortic dimensions (P=0.013) height and weight. Other significant terms were age, heart rate, mean blood pressure, and aortic stiffness (all P<0.001). These findings demonstrate an independent inverse relation between aortic size and pulse pressure in older hypertensive subjects. Differences in aortic dimensions and stiffness between genders do not fully account for the observed blood pressure differences, suggesting that a contributory factor to gender differences in pulse pressure is an increased age-related mismatch in ventricular function and aortic stiffness in women compared with men.

The relationship among work-family conflict and enhancement, organizational work-family culture, and work outcomes for older working women.

This article examines the relationship among work-family conflict and enhancement, organizational work-family culture, and four work outcomes for 489 working women over the age of 50. Survey results from two U.S. health care organizations and one U.S. financial services organization indicate that older working women experience differing amounts of work-to-family conflict, family-to-work conflict, work-to-family enhancement, and family-to-work enhancement. Hypotheses relating organizational work-family culture to work-family conflict and enhancement were partially supported, and hypotheses relating conflict and enhancement to four work outcomes were partially supported. Work-to-family conflict and work-to-family enhancement partially mediate the relationship between organizational work-family culture and selected work outcomes. Implications for theory and practice, limitations of this study, and directions for future research are also presented.

Similar effects of treatment on central and brachial blood pressures in older hypertensive subjects in the Second Australian National Blood Pressure Trial.

The Second Australian National Blood Pressure Trial reported better prognosis for hypertensive subjects randomly assigned to an angiotensin-converting enzyme inhibitor (ACE-I) compared with a diuretic-based regimen despite no difference in brachial blood pressure control. A possible explanation is that there was a difference in central aortic pressures despite similar brachial pressure reductions. We examined this hypothesis in a subset of the Second Australian National Blood Pressure Trial cohort evaluated both before and after 4 years of treatment. The average age of the 479 subjects was 71.6+/-4.7 years (mean+/-SD), and 56% were women. Brachial systolic and pulse pressures after treatment were 145+/-1 (mean+/-SEM), 143+/-1, 72+/-1, and 70+/-1 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were -17+/-2, -16+/-2, -9+/-1, and -7+/-1 mm Hg. None of the differences between diuretic and ACE-I groups were significant. Central arterial pressure waveforms were acquired from carotid tonometry and calibrated from brachial pressures. Central systolic and pulse pressures posttreatment were 144+/-2, 144+/-2, 71+/-2, and 72+/-2 mm Hg for diuretic and ACE-I groups, respectively. The respective changes from pretreatment values were -15+/-2, -17+/-2, -6+/-2, and -8+/-2 mm Hg. None of the differences between diuretic and ACE-I groups were significant. The similarity of central and brachial pressures in this cohort of older hypertensive subjects is most likely because of the influences of age and hypertension in increasing arterial stiffness. There is no evidence that the better prognosis for patients randomly assigned to ACE-I in Second Australian National Blood Pressure Trial resulted from a disproportionate lowering of central blood pressure.

Brachial blood pressure but not carotid arterial waveforms predict cardiovascular events in elderly female hypertensives.

Central arterial waveforms and related indices of large artery properties can be determined with relative ease. This would make them an attractive adjunct in the risk stratification for cardiovascular disease. Although they have been associated with some classical risk factors and the presence of coronary disease, their prospective value in predicting cardiovascular outcomes is unknown. The present study determined the relative predictive value for cardiovascular disease-free survival of large artery properties as compared with noninvasive brachial blood pressure alone in a population of elderly female hypertensive subjects. We measured systemic arterial compliance, central systolic pressure, and carotid augmentation index in a subset of female participants in the Second Australian National Blood Pressure Study (untreated blood pressure 169/88+/-12/8 mm Hg). There were a total of 53 defined events during a median of 4.1 years of follow-up in 484 women with complete measurements. Although baseline blood pressures at the brachial artery predicted cardiovascular disease-free survival (hazard ratio [HR], 2.3; 95% CI, 1.3 to 4.1 for pulse pressure > or =81 versus <81 mm Hg; P=0.01), no such relation was found for carotid augmentation index (HR, 0.80; 95% CI, 0.44 to 1.44; P value not significant) or systemic arterial compliance (HR, 1.25; 95% CI, 0.72 to 2.16; P value not significant). Blood pressure, but not noninvasively measured central arterial waveforms, predict outcome in the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.

Large artery stiffness is not related to plasma cholesterol in older subjects with hypertension.

OBJECTIVE: Previous studies have demonstrated a prognostic role of large artery stiffness in hypertensive subjects and increased stiffness in subjects with coronary artery disease. Although plasma cholesterol is an established risk factor for cardiovascular disease, its relationship with large artery properties in a hypertensive population is unclear. METHODS AND RESULTS: Plasma cholesterol and large artery properties were measured at baseline in a subset of participants of a randomized controlled trial (ANBP2) evaluating hypertension treatment in older (65 to 84 years) subjects. Noninvasive measures of large artery behavior were central augmentation index (AI), systemic arterial compliance (SAC), and transverse expansion of the aortic arch (aortic distensibility). Arterial waveforms acceptable for analysis were obtained in approximately 80% of cases yielding valid measurements of AI in 868, SAC in 846, and aortic distensibility in 680 subjects. Mean total and high-density lipoprotein (HDL) concentrations were 5.5+/-1.0 and 1.4+/-0.5 mmol L(-1). Total and HDL cholesterol and AI were greater in females than males, whereas SAC and aortic distensibility were greater in males. In multiple regression analyses there were no significant associations between stiffness parameters and total or HDL cholesterol. Significant independent associations in such analyses were found for mean arterial blood pressure, gender, age, height, and heart rate, in keeping with previous findings. CONCLUSIONS: In the largest cohort of elderly hypertensive subjects studied to date, plasma cholesterol per se was not associated with large artery stiffness. Such independence from cholesterol increases the potential for artery stiffness measurements to additionally contribute to cardiovascular risk assessment in this population.

Large-artery stiffness contributes to the greater prevalence of systolic hypertension in elderly women.

OBJECTIVES: To determine whether sex differences in large-artery stiffness contribute to the greater prevalence of systolic hypertension in elderly women than in elderly men. DESIGN: During a single visit arterial stiffness was assessed in the unmedicated state using four parameters. PARTICIPANTS: Three hundred seventy-four women with a mean age+/-standard deviation of 72+/-5 and 296 men aged 71+/-5 participated. SETTING: Hypertensive patients were recruited from general practice as part of the second Australian National Blood Pressure Study in Melbourne, Australia. MEASUREMENTS: Large-artery stiffness was assessed using multiple methodologies, including aortic arch stiffness (beta-index) using M-mode ultrasound and arterial compliance and augmentation index using noninvasive carotid pressure and aortic flow measurements. RESULTS: Women had greater carotid and brachial pulse pressure (PP) than men (P<.001), despite higher mean arterial pressure in men. Mean arterial compliance was lower in women (0.20+/-0.12 vs 0.28+/-0.16 mL/mmHg, P<.001) even after correction for aortic area, and aortic arch stiffness was higher (30+/-36 vs 23+/-22; P<.01). Consistent with both a stiffer proximal circulation and a shorter distance to reflection sites, women had higher augmentation index (38+/-11% vs 29+/-12%, P<.001). In multivariate analysis, sex was an independent determinant of all arterial stiffness indices. CONCLUSION: Independently of known confounders, elderly hypertensive women have stiffer large arteries, greater central wave reflection, and higher PP than elderly men. Stiffer large arteries likely contribute to the greater prevalence of systolic hypertension in elderly women and may partly explain the acceleration in postmenopausal cerebrovascular and cardiac complications.

Discovery of N-[2-[2-[[3-methoxy-4-(5-oxazolyl)phenyl]amino]-5-oxazolyl]phenyl]-N-methyl-4- morpholineacetamide as a novel and potent inhibitor of inosine monophosphate dehydrogenase with excellent in vivo activity.

Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats.