Novel approaches to male hormonal contraception

The principle of male hormonal contraception has been investigated for the past 20 years. This thesis reviews what is known already from the literature and presents the results of three new clinical trials investigating different aspects of this approach.These trials were undertaken by myself as a member of the Contraceptive Development Network research group at the University of Edinburgh.MOIS: A clinical trial of male hormonal contraception with a treatment period of 48 weeks. Subjects (n=29) were randomised to receive either 2 MENT Ac implants or 600mg per 12 weeks testosterone pellets in conjunction with 2 etonogestrel implants and outcome measures of sperm count, and reproductive hormone data were collected to assess contraceptive effects. Haematology and biochemistry parameters, prostate volume, PSA, bone density and blood pressure measurements were recorded to assess safety and the effects on androgen dependent tissues. The spermatogenic suppression achieved was similar and effective in both groups. Thereafter, the MENT group failed to maintain suppression and 6 men nnoted loss of libido due to a decline in the release rate of the MENT implants. No adverse effects of MENT on the prostate or bone mass were demonstrated. A small but significant increase in systolic blood pressure was observed in the MENT group and the implications of this remain to be further qualified. In the testosterone group profound and consistent spermatogenic suppression was demonstrated and azoospermia was achieved in all men. An increase in haemoglobin and prostate size and reduction in HDL-C were noted. MENT with progestogen can achieve rapid suppression of spermatogenesis similar to testosterone, but this promising result was not sustained due to a reduction in the MENT release from the implants. This dose of testosterone, compared with previous studies using lower dose with a higher dose of etonogestrel, had non-reproductive side effects without any increase in spermatogenic suppression.Conclusion: These data indicate the importance of the doses of progestogen and testosterone for optimum spermatogenic suppression while minimizing side effects.M016: A randomised controlled trial investigating the effects of gonadotrophin withdrawal and progestogen administration on hormone production, metabolism and action in the human testis. Thirty subjects were randomised to no treatment or gonadotrophin suppression by GnRH antagonist with testosterone (CT) +/- additional administration of the progestogen desogestrel (CTD) for 4 weeks before testicular biopsy. Gene expression was quantified by PCR. Both treatment groups showed similar suppression of gonadotrophins and sperm production and markedly reduced expression of steroidogenic enzymes. Addition of progestogen resulted in expression of 5a-reductase type 1 compared with both controls and the CT group. Inhibin-a and the spermatocytes marker acrosin-binding protein were significantly lower in the CTD but not CT groups, compared with controls, but did not differ between treated groups. Men who showed greater falls in sperm production also showed reduced expression of these three genes but not of the spermatid marker protamine 1.Conclusion: These data provide evidence for direct progestogenic effects on the testis and highlight steroid 5a-reduction and disruption of spermiation as important components of the testicular response to gonadotrophin withdrawal.M017: Investigation of testicular function in normal men and those receiving a male hormonal contraceptive regimen. 20 subjects were recruited and hourly blood samples were taken over 24 hours for measurement of testosterone, inhibin B, LH, FSH and Cortisol. Urinary excretion of testosterone and the testicular steroid epitestosterone was also measured. In the controls, a diurnal variation in serum testosterone and LH but not FSH was detected. The treated group had similar testosterone concentrations but showed no diurnal variation. Periodicity was detected in inhibin B concentrations in 5 controls and in 9 of the treated group. Urinary testosterone excretion did not show a diurnal variation in either group, but this was apparent for epitestosterone with a morning peak in both groups despite the markedly lower excretion in the treated men.Conclusion: The diurnal variation of testosterone in normal men is due to change in secretion rather than clearance and is largely LH driven. An endogenous rhythm in both testicular steroidogenesis (epitestosterone) and Sertoli cell function (Inhibin B) is also present

Terra Incognita

Seduction is not about the culmination or gratification of desire; it is about the thrill of the desire itself. I am the architect of my own wonderland, creating ‘Terra Incognita’— unknown or unexplored territory— through my large scale compositions. I compose my acoustic map with expressive mark making to enhance the experience of movement, space, and perception through the abstract structure. Interlocked with the expressive marks, I pull from music theory to create controlled nonsense, developing an overwhelming geometric pattern that translates sound through movement of time. Where there is order there is language— if you explore, you get rewarded with new findings, just as you are reading a map to depict a code, or reading a clock, counterclockwise. Visualizing this experience of sound in the monochromatic composition, is shown through altering shapes to create abstracted human form within industrial structures to put the viewer in a metaphysical sense of place and rhythm. I am developing a map that seduces you into a garden of euphoria—the essence of Mushin. Communicating movement of vibrations through the act of repetition of design rules, type as form, and musical notation to represent the chaos in our organic environment versus industry. I manipulate the gestural lines to disconnect us with the familiar, taking us into a visual vocabulary of architecture. Using a process of layering reductively and additively is how I deconstruct the perception of my large scale composition with multi media—screen print, wood cut, drawing, painting, bookbinding, and sculptural installation.https://digitalcommons.murraystate.edu/art498/1068/thumbnail.jp

Remembering and Recollecting World War Two: South African Perspectives

Includes bibliographical references.This thesis explores some of the memories and recollections of World War Two in South Africa today. It aims to address an absence of work done on South Africa in relation to World War Two, memory and commemoration. This thesis is as much about the diverse processes of remembrance and recollection as it is about the war itself and assumes that memories of the war can be located in different media. Accordingly the chapters herein are each delegated a media form, from newspapers, literature, memorials, film and photography to oral interviews, in which ‘memories’ of the war are located. The arrangement of the chapters mimics the history of the war’s remembrance in South Africa as it moved from public to private remembrance. This follows the historical context of South Africa from the war period until approximately mid-2013. The white Anglophone experience is given prominence in approaching the subject of commemoration and World War Two in Cape Town. This is motivated by Vivian Bickford- Smith and John Lambert, both of whom recognise it as South Africa’s ‘forgotten identity.’1 Nevertheless other non-white memories of the war are also discussed as important to understanding South Africa’s relationship to it. In particular, the sons and daughters of the Cape Corps briefly feature in this thesis in recognition of a greater Anglophone identity that is not necessarily bound by race. Black recruits are also touched upon as an oft-forgotten group involved in the war. Accordingly this thesis emphasizes that although some experiences and memories were shaped by race, there were others that transcended it. Lastly the different media forms discussed within this thesis are suggestive of technology’s advances and its impact on the way memories are stored and retrieved. Ultimately, despite the fact that the war has fallen out of public remembrance in Cape Town today, this thesis concludes that it remains important to a few groups and individuals for whom it continues to inform a sense of history and identity

Evaluating the implementation of interventions to improve independence in dementia

To understand effects of psychological and social interventions for people with dementia, it is necessary to understand whether interventions are delivered as planned (‘fidelity of delivery’) and engaged with. This thesis aimed to evaluate the implementation of two interventions for people with dementia: the ‘Promoting Independence in Dementia’ intervention (PRIDE) and the ‘Community Occupational Therapy in Dementia-UK’ intervention (COTiD-UK). Three stages were followed: (i) systematically reviewing measures of fidelity and engagement in complex, face-to-face health behaviour change interventions, (ii) developing and using reliable measures to assess fidelity of PRIDE and COTiD-UK, and engagement with PRIDE, and (iii) identifying factors influencing fidelity and engagement and developing recommendations to improve these behaviours. Intervention sessions were audio-recorded and reliably rated for fidelity against fidelity checklists developed for PRIDE and COTiD-UK. Additionally, for PRIDE, dementia advice workers (DAWs) and participants completed checklists after each session. To identify factors influencing fidelity of, and engagement with PRIDE, interviews were conducted with DAWs, people with dementia and their supporters and analysed using thematic analysis and content analysis (informed by the COM-B model). The Behaviour Change Wheel was used to develop recommendations to improve fidelity and engagement. Reliable fidelity checklists were developed for PRIDE and COTiD-UK. Both interventions were delivered with at least moderate fidelity. Participants reported high levels of engagement with PRIDE. Knowledge, providers’ attributes, ease of adaptation of PRIDE in relation to participants’ needs and logistical considerations influenced fidelity. Participants’ attributes, capability and opportunity influenced engagement. Recommendations to improve fidelity and engagement were developed to target barriers of opportunity and psychological capability. This thesis provides an applied example of how behavioural science can be used to evaluate and develop recommendations to improve the implementation of dementia interventions. If effective, recommendations may have the potential to improve implementation and help people to live well with dementia

Modeling of Axial Flow between Eccentric Cylinders

The study of thread annular flow is motivated due to the fact that thread injection is a promising method for placing medical implants within the human body with minimum surgical trauma. The porous thread is stored on a spool and injected within a fluid by applying a pressure gradient. The injection process must be smooth, and lateral deviations of the thread are undesirable. This paper presents a mathematical modeling of the problem and discusses preliminary findings concerning the nature of the basic flow

Transforming the American experience of death: What dreams may come?

There is no means to evaluate the death experience in the US healthcare system. Other countries have established population-wide measures to evaluate and improve the dying experience for patients and their families. With an increasing population of advanced-age persons, changes in sites of death, and a continually fractured healthcare delivery system, there is a need to establish a universal assessment of the quality of death in the US. In this commentary, we outline the need for such an assessment and build off of previous literature on the various existing assessments of the quality of death that have typically been reserved for end-of-life care specialties. Based on the aforementioned reasons and poor performance relative to other nations, there is a need for political attention to assessing the quality of American death experiences for patients and for their families. Absent such a measure, there will never be an incentive to improve the quality of death for patients and their families and the US healthcare system will continue to neglect this important aspect of American life. Experience Framework This article is associated with the Policy & Measurement lens of The Beryl Institute Experience Framework (https://theberylinstitute.org/experience-framework/). Access other PXJ articles related to this lens. Access other resources related to this lens

Family attitudes, actions, decisions and experiences following implementation of deemed consent and the Human Transplantation (Wales) Act 2013:mixed-method study protocol

IntroductionThe Human Transplantation (Wales) Act 2013 (the Act) introduced a ‘soft opt-out’ system of organ donation on 1 December 2015. Citizens are encouraged to make their organ donation decision known during their lifetime. In order to work, the Act and media campaign need to create a context, whereby organ donation becomes the norm, and create a mechanism for people to behave as intended (formally register their decision; consider appointing a representative; convey their donation decision to their families and friends or do nothing—deemed consent). In addition, family members/appointed representatives need to be able to put their own views aside to support the decision of their loved one. The aim of this study is to evaluate initial implementation, outcomes and impact on families and appointed representatives who were approached about organ donation during the first 18 months.Methods and analysisProspective mixed-method coproductive study undertaken with National Health Service Blood and Transplant (NHSBT), and multiple patient/public representatives. The study is designed to collect information on all cases who meet specified criteria (≥18 years, deceased person voluntarily resident in Wales and died in Wales or England) whose family were approached between 1 December 2015 and 31 June 2017). Data for analysis include: NHSBT routinely collected anonymised audit data on all cases; Specialist Nurse in Organ Donation (SNOD) completed anonymised form for all cases documenting their perception of the families’ understanding of the Act, media campaign and outcome of the donation approach; questionnaires and depth interviews with any family member or appointed representative (minimum 50 cases). Additional focus groups and interviews with SNODs. Anonymised donation outcomes and registration activity reports for Wales provide additional context.Ethics and disseminationApproved by NHSBT Research, Innovation and Technology Advisory Group on 23 October 2015; Wales Research Ethics Committee 5 (IRAS190066; Rec Reference 15/WA/0414) on 25 November 2015 and NHSBT R&amp;D Committee (NHSBT ID: AP-15–02) on 24 November 2015.RegistrationThe protocol is registered on the Health and Care Research Wales Clinical Research Portfolio. Study ID number 34396, www.ukctg.nihr.ac.uk</jats:sec

Interleukin-7 restores lymphocytes in septic shock: The IRIS-7 randomized clinical trial

BACKGROUND: A defining pathophysiologic feature of sepsis is profound apoptosis-induced death and depletion of CD4+ and CD8+ T cells. Interleukin-7 (IL-7) is an antiapoptotic common γ-chain cytokine that is essential for lymphocyte proliferation and survival. Clinical trials of IL-7 in over 390 oncologic and lymphopenic patients showed that IL-7 was safe, invariably increased CD4+ and CD8+ lymphocyte counts, and improved immunity. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 (CYT107) in patients with septic shock and severe lymphopenia. Twenty-seven patients at academic sites in France and the United States received CYT107 or placebo for 4 weeks. Primary aims were to determine the safety of CYT107 in sepsis and its ability to reverse lymphopenia. RESULTS: CYT107 was well tolerated without evidence of inducing cytokine storm or worsening inflammation or organ dysfunction. CYT107 caused a 3- to 4-fold increase in absolute lymphocyte counts and in circulating CD4+ and CD8+ T cells that persisted for weeks after drug administration. CYT107 also increased T cell proliferation and activation. CONCLUSIONS: This is the first trial of an immunoadjuvant therapy targeting defects in adaptive immunity in patients with sepsis. CYT107 reversed the marked loss of CD4+ and CD8+ immune effector cells, a hallmark of sepsis and a likely key mechanism in its morbidity and mortality. CYT107 represents a potential new way forward in the treatment of patients with sepsis by restoring adaptive immunity. Such immune-based therapy should be broadly protective against diverse pathogens including multidrug resistant bacteria that preferentially target patients with impaired immunity. TRIAL REGISTRATION: Trials registered at clinicaltrials.gov: NCT02640807 and NCT02797431. FUNDING: Revimmune, NIH National Institute of General Medical Sciences GM44118