Design of an intravaginal ring for the controlled delivery of 17b-estradiol as its 3-acetate ester

Suitable ester prodrugs of 17b-estradiol are identified, thus permitting effective sustained and controlled estrogen replacement therapy (ERT) from an elastomeric, silicone intravaginal ring (IVR). IVR devices of reservoir design were prepared by blending silicone elastomer base with n-propylorthosilicate (cross-linker) and 10% w/w of 17b-estradiol or an ester prodrug, the mix being activated with 0.5% w/w stannous octoate and cured at 808C for 2 min. A rate-controlling membrane was similarly prepared, without the active agent. IVR devices were of cross-sectional diameter 9 mm, outer diameter 54 mm, with core cross-sectional diameter of 2 mm and core length varied as required. Sink conditions were evident for the 17b-estradiol esters in 1.0% aqueous benzalkonium chloride solution. The low release rates into 0.9% w/v saline of the lipophilic valerate and benzoate esters were due to their intrinsically low aqueous solubilities. In vivo, these esters failed to raise plasma estradiol above baseline levels in postmenopausal human volunteers, despite good in vitro release characteristics under sink conditions. The best release rates under sink conditions, in combination with substantial aqueous solubilities as indicated by the release rates into saline, were observed for the acetate and propionate esters. A
combination of drug release characteristics, short plasma half-life and a toxicologically acceptable hydrolysis product indicated that 17b-estradiol-3-acetate was the prodrug of choice for IVR delivery of ERT. In vivo, an IVR device releasing
100 mg/day of estradiol as its 3-acetate ester maintained over 84 days a circulating plasma concentration in the region of 300 pmol l , within the clinically desirable range for ERT.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100kb), rare copy number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1,564 cases and 1,748 controls all from Ireland, and further extended the analysis to include an additional 5,196 UK controls. We found association with duplications at chr20p12.2 (P=0.007) and evidence of replication in large independent European schizophrenia (P=0.052) and UK bipolar disorder case-control cohorts (P=0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11,707 cases and 10 carriers in 21,204 controls (meta-analysis CMH P value=2x10(-4) (odds ratio (OR)=11.3, 95% CI=3.7, ∞)). Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68Mb with similar breakpoints across samples. By haplotype analysis and sequencing we identified a tandem ∼149kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P=2.5x10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

The role of adiposity in cardiometabolic traits:a Mendelian randomization analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

Fruit and vegetable consumption and muscle strength and power during adolescence: a cross-sectional analysis of the Northern Ireland Young Hearts Project 1999-2001

Objectives: To examine the association between fruit and vegetable (FV) consumption and muscle strength and power in an adolescent population. Methods: We conducted a cross-sectional analysis among 1019 boys and 998 girls, aged 12 and 15 years, who participated in The Young Hearts Project. FV consumption (excluding potatoes) was assessed by 7-d diet history. Grip strength and jump power was assessed with a dynamometer and Jump-MD meter, respectively. Associations between FV consumption and strength and power were assessed by regression modelling. Results: Boys and girls with the highest FV intakes (>237.71 g/d and >267.57 g/d, respectively, based on the highest tertile) had significantly higher jump power than those with the lowest intakes (<135.09 g/d and <147.43 g/d, respectively), after adjustment for confounding factors. Although girls with the highest FV intakes had higher grip strength than those with the lowest intakes, no significant independent associations were evident between FV intake and grip strength in boys or girls. Similar findings were observed when FV were analysed separately.Conclusions: Higher FV consumption in this group of adolescents was positively associated with muscle power. There was no independent association between higher FV consumption and muscle strength. Intervention studies are required to determine whether muscle strength and power can be improved through increased FV consumption.

Does vicarious traumatisation affect oncology nurses?:A literature review

It is widely documented that nurses experience work-related stress [Quine, L., 1998. Effects of stress in an NHS trust: a study. Nursing Standard 13 (3), 36-41; Charnley, E., 1999. Occupational stress in the newly qualified staff nurse. Nursing Standard 13 (29), 32-37; McGrath, A., Reid, N., Boore, J., 2003. Occupational stress in nursing. International Journal of Nursing Studies 40, 555-565; McVicar, A., 2003. Workplace stress in nursing: a literature review. Journal of Advanced Nursing 44 (6), 633-642; Bruneau, B., Ellison, G., 2004. Palliative care stress in a UK community hospital: evaluation of a stress-reduction programme. International Journal of Palliative Nursing 10 (6), 296-304; Jenkins, R., Elliott, P., 2004. Stressors, burnout and social support: nurses in acute mental health settings. Journal of Advanced Nursing 48 (6), 622-631], with cancer nursing being identified as a particularly stressful occupation [Hinds, P.S., Sanders, C.B., Srivastava, D.K., Hickey, S., Jayawardene, D., Milligan, M., Olsen, M.S., Puckett, P., Quargnenti, A., Randall, E.A., Tyc, V., 1998. Testing the stress-response sequence model in paediatric oncology nursing. Journal of Advanced Nursing 28 (5), 1146-1157; Barnard, D., Street, A., Love, A.W., 2006. Relationships between stressors, work supports and burnout among cancer nurses. Cancer Nursing 29 (4), 338-345]. Terminologies used to capture this stress are burnout [Pines, A.M., and Aronson, E., 1988. Career Burnout: Causes and Cures. Free Press, New York], compassion stress [Figley, C.R., 1995. Compassion Fatigue. Brunner/Mazel, New York], emotional contagion [Miller, K.I., Stiff, J.B., Ellis, B.H., 1988. Communication and empathy as precursors to burnout among human service workers. Communication Monographs 55 (9), 336-341] or simply the cost of caring (Figley, 1995). However, in the mental health field such as psychology and counselling, there is terminology used to captivate this impact, vicarious traumatisation. Vicarious traumatisation is a process through which the therapist's inner experience is negatively transformed through empathic engagement with client's traumatic material [Pearlman, L.A., Saakvitne, K.W., 1995a. Treating therapists with vicarious traumatization and secondary traumatic stress disorders. In: Figley, C.R. (Ed.), Compassion Fatigue: Coping with Secondary Traumatic Stress Disorder in Those Who Treat the Traumatized. Brunner/Mazel, New York, pp. 150-177]. Trauma not only affects individuals who are primarily present, but also those with whom they discuss their experience. If an individual has been traumatised as a result of a cancer diagnosis and shares this impact with oncology nurses, there could be a risk of vicarious traumatisation in this population. However, although Thompson [2003. Vicarious traumatisation: do we adequately support traumatised staff? The Journal of Cognitive Rehabilitation 24-25] suggests that vicarious traumatisation is a broad term used for workers from any profession, it has not yet been empirically determined if oncology nurses experience vicarious traumatisation. This purpose of this paper is to introduce the concept of vicarious traumatisation and argue that it should be explored in oncology nursing. The review will highlight that empirical research in vicarious traumatisation is largely limited to the mental health professions, with a strong recommendation for the need to empirically determine whether this concept exists in oncology nursing.

Haptic Aurality: Listening in a Digital World

I will question modes of listening in network music performance environments, drawing on my experience as a performer listening in these scenarios. I will situate network listening, which I have previously examined as ‘haptic aurality’ (Schroeder, 2009, 2012, 2013) within the context of current music making, and will refer to changes in compositional practices that draw specific attention to listening. I will show that some of these compositional developments play a determining role in articulating a new discourse of listening. French composer Eric Satie’s concept of Furniture Music (in Duckworth, 2005), Pierre Schaeffer’s ideas on reduced listening (1966), Pauline Oliveros’ deep listening practices (2005) as well as digital music platforms all serve to show a development towards a proliferation in listening experiences. I expand this narrative to listening practices in network performance environments, and identify a specific bodily fragility in listening in and to the network. This fragile state of listening and de-centered kind of performative being allow me to draw parallels to the Japanese art form Butoh (Kasai, 1999, 2000; Kasai and Parsons, 2003) and Elaine Scarry’s metaphor of beauty (Scarry, 2001). My own performance experiences, set within the context of several critical texts, allow me to understand network[ed] listening as an ideal corporeal state, which offers a rethinking of linear conceptions of the other and a subject’s own relation with her world. Ultimately, network[ed] listening posits listening as a corporeal and multi-dimensional experience that is continuously being re-shaped by technological, socio-political and cultural concerns.

French literature, from 1945 to 1999

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