Laser doppler perfusion imaging of the normal and diseased vulva.

Vulval lichen sclerosus (LS) and high-grade intraepithelial neoplasia (VIN 3) are two common and distressing diseases. Significant morbidity is caused by symptoms of persistent pruritus and surgical treatment of skin areas suspicious of malignancy. The risk of developing cancer in a background of LS and VIN 3 is poorly defined. The methods currently available for clinical assessment of the vulva are limited. There is abundant research on the application of the LASER Doppler technique - laser Doppler Flowmetry (LDF) - showing changes in perfusion within the small blood vessels of the skin as a useful parameter for more accurate disease classification. There is also research on immunohistochemical microvessel density (MVD) studies showing increases in blood supply in tissues prone to develop cancer or as a prognostic marker of cancer outcome. The Laser Doppler perfusion imager (LDPI) provides a rapid, real time, non-invasive and non-contact method to measure skin blood flow in an area as opposed to a single point by the LDF, making the LDPI more suitable for application to the vulva. This thesis reports for the first time, the application of the LDPI to the vulva. Initially the LDPI was applied to the clinically normal vulva to study perfusion variance related to menstrual cycle, age and local skin temperature provocation. The application was then extended to vulval disease, LS and VIN 3, and validated against morphological differences in MVD. The LDPI and MVD studies suggest that in VIN 3 there is an actual increase in skin perfusion. In LS the situation is more complex and suggests that the LDPI measured perfusion at a greater depth than the MVD. Studies on base line perfusion variance of vulval LS to topical therapy show that there is no overall difference in baseline perfusion in spite of symptom improvement. Temperature provocation studies suggest differences in skin blood flow response in diseased compared to the normal vulva

Barriers to the management of sexual dysfunction among people with psychosis: analysis of qualitative data from the REMEDY trial

Background: More than half of people who use antipsychotic medication for psychosis report having sexual dysfunction. The REMEDY trial aimed to find out if switching antipsychotic medication provides an effective way to reduce sexual dysfunction among people with psychosis. We set out to recruit 216 participants over a two-year period, but recruitment was stopped after an extended 12-month pilot phase, during which we recruited only 10 participants. As part of a nested process evaluation, we conducted qualitative interviews with front-line clinicians to examine barriers to recruitment to the trial. Methods: We developed a semi-structured interview schedule to explore staff views on factors that influenced whether they referred potential participants to the study. We interviewed a purposive sample of 51 staff from four National Health Service (NHS) Trusts in England, ensuring a range of different backgrounds, seniority, and levels of involvement in the trial. Audio recordings of interviews were transcribed for verbatim, and data were analysed using an inductive approach to thematic analysis. Results: Nine interconnected themes were generated. Six themes concerned barriers to recruitment; including; prioritising patients’ mental stability, mutual discomfort and embarrassment about discussing a “taboo” subject, and concerns about unintended consequences of asking people with psychosis about their sexual functioning. Three themes, including the quality of treatment relationships and strategies for opening dialogue suggested ways to improve recognition of these “hidden” side effects. Conclusion: The identification and management of sexual dysfunction among people with psychosis are not priorities for mental health services in England at this time. Many staff working in front-line services feel unprepared and uncomfortable asking people with psychosis about these problems. While greater use of screening tools may improve the identification of sexual dysfunction among people with psychosis, the evaluation and implementation of interventions to manage them will continue to be challenging unless NHS leaders and senior clinicians demonstrate greater commitment to changing current clinical practice. Trial registration: Current Controlled Trials ISRCTN12307891

Barriers to the management of sexual dysfunction among people with psychosis: analysis of qualitative data from the REMEDY trial

Background: More than half of people who use antipsychotic medication for psychosis report having sexual dysfunction. The REMEDY trial aimed to find out if switching antipsychotic medication provides an effective way to reduce sexual dysfunction among people with psychosis. We set out to recruit 216 participants over a two-year period, but recruitment was stopped after an extended 12-month pilot phase, during which we recruited only 10 participants. As part of a nested process evaluation, we conducted qualitative interviews with front-line clinicians to examine barriers to recruitment to the trial. Methods: We developed a semi-structured interview schedule to explore staff views on factors that influenced whether they referred potential participants to the study. We interviewed a purposive sample of 51 staff from four National Health Service (NHS) Trusts in England, ensuring a range of different backgrounds, seniority, and levels of involvement in the trial. Audio recordings of interviews were transcribed for verbatim, and data were analysed using an inductive approach to thematic analysis. Results: Nine interconnected themes were generated. Six themes concerned barriers to recruitment; including; prioritising patients’ mental stability, mutual discomfort and embarrassment about discussing a “taboo” subject, and concerns about unintended consequences of asking people with psychosis about their sexual functioning. Three themes, including the quality of treatment relationships and strategies for opening dialogue suggested ways to improve recognition of these “hidden” side effects. Conclusion: The identification and management of sexual dysfunction among people with psychosis are not priorities for mental health services in England at this time. Many staff working in front-line services feel unprepared and uncomfortable asking people with psychosis about these problems. While greater use of screening tools may improve the identification of sexual dysfunction among people with psychosis, the evaluation and implementation of interventions to manage them will continue to be challenging unless NHS leaders and senior clinicians demonstrate greater commitment to changing current clinical practice. Trial registration: Current Controlled Trials ISRCTN12307891

Development of a Novel Virtual Screening Cascade Protocol to Identify Potential Trypanothione Reductase Inhibitors

The implementation of a novel sequential computational approach that can be used effectively for virtual screening and identification of prospective ligands that bind to trypanothione reductase (TryR) is reported. The multistep strategy combines a ligand-based virtual screening for building an enriched library of small molecules with a docking protocol (AutoDock, X-Score) for screening against the TryR target. Compounds were ranked by an exhaustive conformational consensus scoring approach that employs a rank-by-rank strategy by combining both scoring functions. Analysis of the predicted ligand-protein interactions highlights the role of bulky quaternary amine moieties for binding affinity. The scaffold hopping (SHOP) process derived from this computational approach allowed the identification of several chemotypes, not previously reported as antiprotozoal agents, which includes dibenzothiepine, dibenzooxathiepine, dibenzodithiepine, and polycyclic cationic structures like thiaazatetracyclo-nonadeca-hexaen-3-ium. Assays measuring the inhibiting effect of these compounds on T. cruzi and T. brucei TryR confirm their potential for further rational optimization

Persistence of Fimbrial Tissue on the Ovarian Surface Following Salpingectomy

BACKGROUND: Salpingectomy is recommended as a risk-reducing strategy for epithelial tubo-ovarian cancer. The gold standard procedure is complete tubal excision. OBJECTIVE: To assess the presence of residual fimbrial/tubal tissue on ovarian surfaces following salpingectomy. DESIGN: Prospective analysis of patients undergoing salpingo-oophorectomy +/- hysterectomy for benign indications, early cervical cancer or low risk endometrial cancer at a UK National Health Service Trust. Salpingectomy +/- hysterectomy was performed initially, followed by oophorectomy within the same operation. Separately retrieved tubes and ovaries were serially sectioned and completely examined histologically. The main outcome measure was histologically identified fimbrial/ tubal tissue on ovarian surface. Chi-square/Fisher's exact tests evaluated categorical variables (SPSS-23). RESULTS: 25 consecutive cases (mean age= 54.8 years (SD=5.0), comprising 41 adnexae (9= unilateral, 16= bilateral) were analysed. 17 (68.0%), 5 (20.0%) and 3 (12.0%), procedures were performed by consultant gynaecologists, subspecialty/specialist trainees and consultant gynaecological oncologists respectively. 12/25 (48.0%) were laparoscopic and 13/25 (52.0%) involved laparotomy. 4/25 (16.0%, CI: 4.5%, 36.1%) patients or 4/41 (9.8%, CI: 2.7%, 23.1%) adnexae showed residual microscopic fimbrial tissue on the ovarian surface. Tubes/ ovaries were free of adhesions in 23 cases. Two cases had dense adnexal adhesions but neither had residual fimbrial tissue on the ovary. Residual fimbrial tissue was not significantly associated with surgical route or experience; (consultant= 3/20 (15%), trainee= 1/5 (20%), p=1.0). CONCLUSION: Residual fimbrial tissue remains on the ovary following salpingectomy in a significant proportion of cases and could impact the level of risk-reduction obtained

Dynamics of notch pathway expression during mouse testis post-natal development and along the spermatogenic cycle

Articles in International JournalsThe transcription and expression patterns of Notch pathway components (Notch 1–3, Delta1 and 4, Jagged1) and effectors (Hes1, Hes2, Hes5 and Nrarp) were evaluated (through RT-PCR and IHC) in the mouse testis at key moments of post-natal development, and along the adult spermatogenic cycle. Notch pathway components and effectors are transcribed in the testis and expressed in germ, Sertoli and Leydig cells, and each Notch component shows a specific cell-type and timewindow expression pattern. This expression at key testis developmental events prompt for a role of Notch signaling in prepubertal spermatogonia quiescence, onset of spermatogenesis, and regulation of the spermatogenic cycle

Publication Records of Faculty Promoted to Professor: Evidence from the UK Accounting and Finance Academic Community

This study investigates the publication profiles of 140 accounting and finance faculty promoted to the senior rank of professor at UK and Irish universities during the period 1992 to 2007. On average, approximately 9 papers in Association of Business Schools (ABS) (2008)-listed journals, with 5 at the highest 3*/4* quality levels in a portfolio of 20 outputs are required for promotion to professor. Multivariate analysis provides evidence that publication requirements in terms of ABS ranked journal papers have increased over time, an effect attributed to the government research assessment exercise. There is no evidence that requirements differ for: internal versus external promotion, male versus female candidates; accounting versus finance professors, research intensity of institution peer group; or government research ranking of unit. There is also no evidence of a substitution effect in relation to increased recent publication history, quantity of non-ABS outputs or sole-authorship, all of which show a significant complementary effect. It is noted that there is very limited overlap in the UK and US publication journal sets, suggesting underlying geographically-based paradigm differences. The benchmarks provided in this study are informative in a range of decision settings: recruitment; those considering making an application for promotion to a chair and those involved in promotion panels; cross-disciplinary comparisons; and resource allocation. The evidence presented also contributes to the emerging policy debates concerning the aging demographic profile of accounting faculty, the management of academic labour and the Research Excellence Framework

Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.This work was funded by ERC starting grant Relieve IMDs (L.V., N.H.), the Cambridge Hospitals National Institute for Health Research Biomedical Research Center (L.V., N.H., F.S.), the Evelyn trust (N.H.) and the EU Fp7 grant TissuGEN (M.CDB.). FS has been supported by an Addenbrooke’s Charitable Trust Clinical Research Training Fellowship and a joint MRC-Sparks Clinical Research Training Fellowship.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nbt.327

Switching antipsychotic medication to reduce sexual dysfunction in people with psychosis: the REMEDY RCT

BackgroundSexual dysfunction is common among people who are prescribed antipsychotic medication for psychosis. Sexual dysfunction can impair quality of life and reduce treatment adherence. Switching antipsychotic medication may help, but the clinical effectiveness and cost-effectiveness of this approach is unclear.ObjectiveTo examine whether or not switching antipsychotic medication provides a clinically effective and cost-effective method to reduce sexual dysfunction in people with psychosis.DesignA two-arm, researcher-blind, pilot randomised trial with a parallel qualitative study and an internal pilot phase. Study participants were randomised to enhanced standard care plus a switch of antipsychotic medication or enhanced standard care alone in a 1?:?1 ratio. Randomisation was via an independent and remote web-based service using dynamic adaptive allocation, stratified by age, gender, Trust and relationship status.SettingNHS secondary care mental health services in England.ParticipantsPotential participants had to be aged ??18 years, have schizophrenia or related psychoses and experience sexual dysfunction associated with the use of antipsychotic medication. We recruited only people for whom reduction in medication dosage was ineffective or inappropriate. We excluded those who were acutely unwell, had had a change in antipsychotic medication in the last 6 weeks, were currently prescribed clozapine or whose sexual dysfunction was believed to be due to a coexisting physical or mental disorder.InterventionsSwitching to an equivalent dose of one of three antipsychotic medications that are considered to have a relatively low propensity for sexual side effects (i.e. quetiapine, aripiprazole or olanzapine). All participants were offered brief psychoeducation and support to discuss their sexual health and functioning.Main outcome measuresThe primary outcome was patient-reported sexual dysfunction, measured using the Arizona Sexual Experience Scale. Secondary outcomes were researcher-rated sexual functioning, mental health, side effects of medication, health-related quality of life and service utilisation. Outcomes were assessed 3 and 6 months after randomisation. Qualitative data were collected from a purposive sample of patients and clinicians to explore barriers to recruitment.Sample sizeAllowing for a 20% loss to follow-up, we needed to recruit 216 participants to have 90% power to detect a 3-point difference in total Arizona Sexual Experience Scale score (standard deviation 6.0 points) using a 0.05 significance level.ResultsThe internal pilot was discontinued after 12 months because of low recruitment. Ninety-eight patients were referred to the study between 1 July 2018 and 30 June 2019, of whom 10 were randomised. Eight (80%) participants were followed up 3 months later. Barriers to referral and recruitment included staff apprehensions about discussing side effects, reluctance among patients to switch medication and reticence of both staff and patients to talk about sex.LimitationsInsufficient numbers of participants were recruited to examine the study hypotheses.ConclusionsIt may not be possible to conduct a successful randomised trial of switching antipsychotic medication for sexual functioning in people with psychosis in the NHS at this time.Future workResearch examining the acceptability and effectiveness of adjuvant phosphodiesterase inhibitors should be considered.Trial registrationCurrent Controlled Trials ISRCTN12307891.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 44. See the NIHR Journals Library website for further project information