Statutory Wills:Doing the right thing under the Mental Capacity Act 2005

SummaryStatutory wills are made under the Mental Capacity Act 2005 (MCA) for persons who lack testamentary capacity. Mental health practitioners are likely to be familiar with many of the provisions of the MCA and the test for testamentary capacity. However, they may not have encountered statutory wills. This article explains the procedure for applying for a statutory will, including the role of medical practitioners. Salient legal cases are summarised to highlight the difficulties in applying a best interests framework for decision-making in the context of statutory wills. Finally, this article considers how the United Nations Convention on the Rights of Persons with Disabilities (CRPD) might affect not only on statutory wills, but also the wider provisions of the MCA.Learning Objectives• Be able to explain statutory wills and the application procedure to a patient or carer• Understand the differences between the test for testamentary capacity (as established inBanks v Goodfellow(1870)) and assessing capacity under the MCA• Appreciate how the CRPD might affect the decision-making process, not only for statutory wills but for all decisions made under the MCA</jats:sec

Evaluation Research and Institutional Pressures: Challenges in Public-Nonprofit Contracting

This article examines the connection between program evaluation research and decision-making by public managers. Drawing on neo-institutional theory, a framework is presented for diagnosing the pressures and conditions that lead alternatively toward or away the rational use of evaluation research. Three cases of public-nonprofit contracting for the delivery of major programs are presented to clarify the way coercive, mimetic, and normative pressures interfere with a sound connection being made between research and implementation. The article concludes by considering how public managers can respond to the isomorphic pressures in their environment that make it hard to act on data relating to program performance.This publication is Hauser Center Working Paper No. 23. The Hauser Center Working Paper Series was launched during the summer of 2000. The Series enables the Hauser Center to share with a broad audience important works-in-progress written by Hauser Center scholars and researchers

Proceedings of the 13th annual conference of INEBRIA

CITATION: Watson, R., et al. 2016. Proceedings of the 13th annual conference of INEBRIA. Addiction Science & Clinical Practice, 11:13, doi:10.1186/s13722-016-0062-9.The original publication is available at https://ascpjournal.biomedcentral.comENGLISH SUMMARY : Meeting abstracts.https://ascpjournal.biomedcentral.com/articles/10.1186/s13722-016-0062-9Publisher's versio

Transiently activated human regulatory T cells upregulate BCL-XL expression and acquire a functional advantage in vivo

Regulatory T cells (Tregs) can control excessive or undesirable immune responses toward autoantigens, alloantigens, and pathogens. In transplantation, host immune responses against the allograft are suppressed through the use of immunosuppressive drugs, however this often results in life-threatening side effects including nephrotoxicity and an increased incidence of cancer and opportunistic infections. Tregs can control graft-vs.-host disease and transplant rejection in experimental models, providing impetus for the use of Tregs as a cellular therapy in clinical transplantation. One of the major barriers to the widespread use of Treg cellular therapy is the requirement to expand cells ex vivo to large numbers in order to alter the overall balance between regulatory and effector cells. Methods that enhance suppressive capacity thereby reducing the need for expansion are therefore of interest. Here, we have compared the function of freshly-isolated and ex vivo-manipulated human Tregs in a pre-clinical humanized mouse model of skin transplantation. Sorted human CD127loCD25+CD4+ Tregs were assessed in three different conditions: freshly-isolated, following transient in vitro activation with antiCD3/antiCD28 beads or after ex vivo-expansion for 2 weeks in the presence of antiCD3/antiCD28 beads and recombinant human IL2. While ex vivo-expansion of human Tregs increased their suppressive function moderately, transient in vitro-activation of freshly isolated Tregs resulted in a powerful enhancement of Treg activity sufficient to promote long-term graft survival of all transplants in vivo. In order to investigate the mechanisms responsible for these effects, we measured the expression of Treg-associated markers and susceptibility to apoptosis in activated Tregs. Transiently activated Tregs displayed enhanced survival and proliferation in vitro and in vivo. On a molecular level, Treg activation resulted in an increased expression of anti-apoptotic BCL2L1 (encoding BCL-XL) which may be at least partially responsible for the observed enhancement in function. Our results suggest that in vitro activation of human Tregs arms them with superior proliferative and survival abilities, enabling them to more effectively control alloresponses. Importantly, this transient activation results in a rapid functional enhancement of freshly-isolated Tregs, thereby providing an opportunity to eliminate the need for in vitro expansion in select circumstances. A protocol employing this technique would therefore benefit from a reduced requirement for large cell numbers for effective therapy

Therapeutic human Treg migrate to the human skin allograft and its draining lymph node to prevent skin destruction.

<p>(<b>A</b>) Therapy with <i>ex vivo</i>-expanded human Treg promotes the long-term survival of human skin allografts in a dose-dependent manner (**<i>p</i> = 0.0061; *<i>p</i> = 0.0386, median survival time = MST). In human skin allografts from Treg-treated mice at day 40 post-adoptive transfer of cells, an increase in the number of human CD4⁺FOXP3⁺ (huFOXP3⁺) cells is present in the skin allograft, as measured by (<b>B</b>) immunohistochemistry and (<b>C</b>) qPCR for <i>FOXP3</i>. (<b>D</b>) HuFOXP3⁺ cells are visualised in regulated human skin allografts over 100 days post-adoptive cellular transfer. (<b>E</b>) Mice received a human skin allograft and an injection of CD4⁺-depleted PBMC (-CD4⁺ group), CD4⁺-depleted PBMC with human Treg (+Treg group), or unmanipulated PBMC alone. In this system where the only human CD4⁺ (huCD4⁺) cells present are Treg, huCD4⁺ cells accumulate in the skin allograft draining lymph node at day 21 post-adoptive transfer in mice receiving Treg (n = 3 mice per group, **<i>p</i> = 0.0062, *<i>p</i> = 0.0144, data represented as values and calculated means). (<b>F</b>) Schematic representation of the experimental plan for (<b>G</b>), where mice received a human skin graft and an injection of PBMC, PBMC with Treg, or no cells. Mice receiving PBMC alone rejected their skin allografts. Skin grafts on mice receiving PBMC with Treg (‘Treg-treated allografts’) or no cells (‘Control allografts’) survived long-term. These skin grafts were retransplanted onto mice that were then reconstituted with PBMC. Skin re-transplants from Treg-treated mice survived long-term (<i>p</i> = 0.0169).</p

Skin-homing <i>CLA⁺ Treg are more effective at preventing allograft destruction than CLA</i>⁻<i>Treg.</i>

<p>(<b>A</b>) APB-derived Treg were sorted into CLA⁺ and CLA⁻ subpopulations and adoptively transferred together with non-autologous PBMC at a 5∶1 ratio of PBMC to Treg into mice previously transplanted with a human skin allograft. A further group of mice received unsorted APB-derived Treg. While CLA⁻ Treg treatment resulted in an MST of 71, treatment with CLA⁺ Treg significantly prolonged skin allograft survival to beyond 100 days (<i>p</i> = 0.0389). Mice receiving unsorted Treg achieved a similar MST to those receiving CLA⁻ Treg (72 days, <i>p</i> = 0.1827). (<b>B</b>) In mice treated with CLA⁺ Treg, a higher frequency of CD4⁺CD25^hi cells was detected within the graft on day 100 compared to mice treated with CLA⁻ Treg (<i>p</i> = 0.031).</p