Development of a novel approach to expand umbilical cord blood-derived haematopoietic stem/progenitor cells ex vivo for clinical transplantation

Umbilical cord blood (UCB) is a well established alternative source of haematopoietic stem/progenitor cells (HSPC) for haematopoietic stem cell transplantation (HSCT). One factor limiting the wider use of UCB for transplantation is the relatively low cell dose from a UCB unit compared to bone marrow (BM) and peripheral blood (PB). To overcome this barrier, many strategies have been tested to expand HSPC numbers ex vivo. The aims of this thesis were to define the phenotypic, functional and transcriptional changes that occur during ex vivo expansion of UCB HSPC and investigate how activation of the Wingless (Wnt) pathway via GSK-3 inhibition can provide a novel approach to improve transplantation outcomes using expanded cells. In vitro and in vivo models of HSPC function were used to evaluate the impact of expansion and GSK-3 inhibition on progenitor function while gene array technology was used to investigate potential molecular mechanisms.We have shown that expansion of UCB HSPC results in a loss of primitive phenotype, an increase in progenitors with reduced function and a shift in transcriptional profile from ‘stem-like quiescent’ to ‘divide and differentiate’. Brief treatment of expansion cultures with a GSK-3 inhibitor resulted in delayed cell cycle progression which translated into improved PB and BM repopulation. Gene expression analysis revealed modulation of Notch and Tie2 pathways, suggesting their potential role in improving stem cell engraftment. In addition, down-regulation of cyclin D1 and upregulation of CDK inhibitor p57 known to be important in maintenance of quiescence was observed.This work is a timely reminder of the medical revolution that E. Donnall Thomas pioneered in the 1950’s, paving the way for successful treatment of those with haematological malignancies and other blood disorders. In addition, the year 2013 marked the 25th anniversary of the first UCB transplant that took place in France in October 1988. Since then over 600,000 UCB units have been banked and more than 30,000 UCB transplants performed worldwide. This thesis contributes to the understanding of HSPC biology and how this can be modulated to improve clinical transplant outcomes in the future

Critical Contextual Elements in Facilitating and Achieving Success with a Person-Centred Care Intervention to Support Antipsychotic Deprescribing for Older People in Long-Term Care

Antipsychotic and other tranquilising medicines are prescribed to help care staff manages behaviour in one-quarter of older people living in Australian long-term care homes. While these medicines pose significant health risks, particularly for people with dementia, reliance on their use occurs when staff are not educated to respond to resident behaviour using nonpharmacological approaches. The Halting Antipsychotic use in Long-Term care (HALT) single-arm study was undertaken to address this issue with 139 people 60 years and over with behaviours of concern for staff living in 24 care homes. A train-the-trainer approach delivered person-centred care education and support for 22 HALT (nurse) champions and 135 direct care staff, dementia management education for visiting general practitioners (GP) and pharmacists, use of an individualised deprescribing protocol for residents, and awareness-raising for the resident’s family. The HALT champions completed open-ended questionnaires and semistructured interviews to identify the contextual elements they considered most critical to facilitating, educating care staff, and achieving success with the study intervention. They reported that person-centred approaches helped care staff to respond proactively to resident behaviours in the absence of antipsychotic medicines; the champions considered that this required strong managerial support, champion empowerment to lead change, reeducation of care staff, and the cooperation of families and GPs

Antipsychotic Deprescription for Older Adults in Long-term Care: The HALT Study

OBJECTIVES: Despite limited efficacy and significant safety concerns, antipsychotic medications are frequently used to treat behavioral and psychological symptoms of dementia (BPSD) in long-term residential care. This study evaluates the sustained reduction of antipsychotic use for BPSD through a deprescribing intervention and education of health care professionals. DESIGN: Repeated-measures, longitudinal, single-arm study. SETTING: Long-term residential care of older adults. PARTICIPANTS: Nursing staff from 23 nursing homes recruited 139 residents taking regular antipsychotic medication for ≥3 months, without primary psychotic illness, such as schizophrenia or bipolar disorder, or severe BPSD. INTERVENTION: An antipsychotic deprescribing protocol was established. Education of general practitioners, pharmacists, and residential care nurses focused on nonpharmacological prevention and management of BPSD. MEASUREMENTS: The primary outcome was antipsychotic use over 12-month follow-up; secondary outcomes were BPSD (Neuropsychiatric Inventory, Cohen-Mansfield Agitation Inventory, and social withdrawal) and adverse outcomes (falls, hospitalizations, and cognitive decline). RESULTS: The number of older adults on regular antipsychotics over 12 months reduced by 81.7% (95% confidence interval: 72.4-89.0). Withdrawal was not accompanied by drug substitution or a significant increase in pro-re-nata antipsychotic or benzodiazepine administration. There was no change in BPSD or in adverse outcomes. CONCLUSION: In a selected sample of older adults living in long-term residential care, sustained reduction in regular antipsychotic use is feasible without an increase of BPSD.status: publishe