An impact evaluation of an education bundle for patients at risk of developing venous thromboembolism.

Aim: Among hospitalized patients, venous thromboembolism (VTE) is a preventable cause of morbidity and mortality. This study analyzed the effects of a large-scale adoption of a prompt response and education protocol to increase VTE prophylaxis adherence in the USA. Methods: A Markov model was developed that simulates outcomes and costs of delivering a VTE education bundle versus not, to hospitalized at-risk patients. Results: The education bundle could avert more than 134,000 VTEs, 552,000 hospital days and 19,000 deaths over 5 years. Patients could save 13 million hours in work absenteeism and travel time, valued at US$237 million. Total societal savings could amount to US$2.8 billion. In scenario analyses with assumed lower-effectiveness estimates, the bundle averts 16,000 VTEs, 67,000 hospital days and 2000 deaths. Conclusion: A nationwide rollout of an education bundle to reduce missed doses of prescribed prophylaxis could improve quality of care, resulting in a decline in VTEs and mortality.

In a previous study, an education bundle was designed to increase administration of medication to prevent blood clotting among hospitalized patients at risk of venous thromboembolism (VTE). The education bundle led to a decrease in patients missing those needed doses of medication. The current study estimates the economic impacts of a nationwide rollout of the education bundle for patients at risk of VTE. The results show that if the education bundle were rolled out nationally, it could result in 134,000 fewer VTEs, 552,000 fewer days spent in the hospital and 19,000 fewer deaths over 5 years. As a result of reduced medical care, less time off work, and informal caregiving needed, societal cost savings could be as much as US$2.8 billion.

Implementation Cost Analysis of an Intensive Comprehensive Aphasia Program.

OBJECTIVE: To identify and measure the costs of implementing an intensive comprehensive aphasia program (ICAP). DESIGN: Retrospective cost analysis of a clinical ICAP. Cost inputs were gathered directly from the provider of the ICAP. We performed several sensitivity analyses to examine major cost drivers and to separate start-up costs from operating costs. SETTING: Urban rehabilitation hospital. PARTICIPANTS: Adults with aphasia. MAIN OUTCOME MEASURES: Total implementation cost to the provider. RESULTS: Implementation cost of running the ICAP for the first time was $133,644 for a cohort of 8 participants with aphasia. Break-even charges per participant ranged from $15,278 for 10 participants to $19,700 for 6 participants. After accounting for start-up costs and efficiencies gained, the fourth and subsequent programs were estimated to cost $84,855 each. The majority of the costs were personnel costs, and the cost of the speech language pathologist's time was the main cost driver in this analysis. CONCLUSIONS: Initial implementation costs are high compared with subsequent programs. Future work should examine effectiveness of an ICAP compared with other treatments to determine its cost-effectiveness.

Cost-Effectiveness Analysis of Adjuvant Therapy for BRAF-Mutant Resected Stage III Melanoma in Medicare Patients.

BACKGROUND: Adjuvant therapy for stage III melanoma improves several measures of patient survival. However, decisions regarding inclusion of adjuvant therapies in the formularies of public payers necessarily consider the cost-effectiveness of those treatments. The objective of this study is to evaluate the cost-effectiveness of four recently approved adjuvant therapies for BRAF-mutant stage III melanoma in the Medicare patient population. METHODS: In this cost-effectiveness analysis, a Markov microsimulation model was used to simulate the healthcare trajectory of patients randomized to receive either first-line targeted therapy (dabrafenib-trametinib) or immunotherapy (ipilimumab, nivolumab, or pembrolizumab). The base case was a 65-year-old Medicare patient with BRAF V600E-mutant resected stage III melanoma. Possible health states included recurrence-free survival, adverse events, local recurrence, distant metastases, and death. Transition probabilities were determined from published clinical trials. Costs were estimated from reimbursement rates reported by CMS and the Red Book drug price database. Primary outcomes were costs (US$), life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Model robustness was evaluated using one-way and probabilistic sensitivity analyses. RESULTS: Dabrafenib-trametinib provided 1.83 QALYs over no treatment and 0.23 QALYs over the most effective immunotherapy, pembrolizumab. Dabrafenib-trametinib was associated with an ICER of $95,758/QALY over no treatment and $285,863/QALY over pembrolizumab. Pembrolizumab yielded an ICER of $68,396/QALY over no treatment and dominated other immunotherapies. CONCLUSIONS: Pembrolizumab is cost-effective at a conventional willingness-to-pay (WTP) threshold, but dabrafenib-trametinib is not. Though dabrafenib-trametinib offers incremental QALYs, optimization of drug pricing is necessary to ensure dabrafenib-trametinib is accessible at an acceptable WTP threshold.

Protocol for the economic evaluation of a complex intervention to improve the mental health of maltreated infants and children in foster care in the UK (The BeST? services trial).

INTRODUCTION: Children who have experienced abuse and neglect are at increased risk of mental and physical health problems throughout life. This places an enormous burden on individuals, families and society in terms of health services, education, social care and judiciary sectors. Evidence suggests that early intervention can mitigate the negative consequences of child maltreatment, exerting long-term positive effects on the health of maltreated children entering foster care. However, evidence on cost-effectiveness of such complex interventions is limited. This protocol describes the first economic evaluation of its kind in the UK. METHODS AND ANALYSIS: An economic evaluation alongside the Best Services Trial (BeST?) has been prospectively designed to identify, measure and value key resource and outcome impacts arising from the New Orleans intervention model (NIM) (an infant mental health service) compared with case management (CM) (enhanced social work services as usual). A within-trial economic evaluation and long-term model from a National Health Service/Personal Social Service and a broader societal perspective will be undertaken alongside the National Institute for Health Research (NIHR)-Public Health Research Unit (PHRU)-funded randomised multicentre BeST?. BeST? aims to evaluate NIM compared with CM for maltreated children entering foster care in a UK context. Collection of Paediatric Quality of Life Inventory (PedsQL) and the recent mapping of PedsQL to EuroQol-5-Dimensions (EQ-5D) will facilitate the estimation of quality-adjusted life years specific to the infant population for a cost-utility analysis. Other effectiveness outcomes will be incorporated into a cost-effectiveness analysis (CEA) and cost-consequences analysis (CCA). A long-term economic model and multiple economic evaluation frameworks will provide decision-makers with a comprehensive, multiperspective guide regarding cost-effectiveness of NIM. The long-term population health economic model will be developed to synthesise trial data with routine linked data and key government sector parameters informed by literature. Methods guidance for population health economic evaluation will be adopted (lifetime horizon, 1.5% discount rate for costs and benefits, CCA framework, multisector perspective). ETHICS AND DISSEMINATION: Ethics approval was obtained by the West of Scotland Ethics Committee. Results of the main trial and economic evaluation will be submitted for publication in a peer-reviewed journal as well as published in the peer-reviewed NIHR journals library (Public Health Research Programme). TRIAL REGISTRATION NUMBER: NCT02653716; Pre-results.

Paving the way for the use of the SDQ in economic evaluations of school-based population health interventions: an empirical analysis of the external validity of SDQ mapping algorithms to the CHU9D in an educational setting.

PURPOSE: The Strengths and Difficulties Questionnaire (SDQ) is a behavioural screening tool for children. The SDQ is increasingly used as the primary outcome measure in population health interventions involving children, but it is not preference based; therefore, its role in allocative economic evaluation is limited. The Child Health Utility 9D (CHU9D) is a generic preference-based health-related quality of-life measure. This study investigates the applicability of the SDQ outcome measure for use in economic evaluations and examines its relationship with the CHU9D by testing previously published mapping algorithms. The aim of the paper is to explore the feasibility of using the SDQ within economic evaluations of school-based population health interventions. METHODS: Data were available from children participating in a cluster randomised controlled trial of the school-based roots of empathy programme in Northern Ireland. Utility was calculated using the original and alternative CHU9D tariffs along with two SDQ mapping algorithms. t tests were performed for pairwise differences in utility values from the preference-based tariffs and mapping algorithms. RESULTS: Mean (standard deviation) SDQ total difficulties and prosocial scores were 12 (3.2) and 8.3 (2.1). Utility values obtained from the original tariff, alternative tariff, and mapping algorithms using five and three SDQ subscales were 0.84 (0.11), 0.80 (0.13), 0.84 (0.05), and 0.83 (0.04), respectively. Each method for calculating utility produced statistically significantly different values except the original tariff and five SDQ subscale algorithm. CONCLUSION: Initial evidence suggests the SDQ and CHU9D are related in some of their measurement properties. The mapping algorithm using five SDQ subscales was found to be optimal in predicting mean child health utility. Future research valuing changes in the SDQ scores would contribute to this research.

Examining the feasibility of an economic analysis of dyadic developmental psychotherapy for children with maltreatment associated psychiatric problems in the United Kingdom.

BACKGROUND: Children with maltreatment associated psychiatric problems are at increased risk of developing behavioural or mental health disorders. Dyadic Developmental Psychotherapy (DDP) was proposed as treatment for children with maltreatment histories in the USA, however, being new to the UK little is known of its effectiveness or cost-effectiveness. As part of an exploratory study, this paper explores the feasibility of undertaking economic analysis of DDP in the UK. METHODS: Feasibility for economic analysis was determined by ensuring such analysis could meet key criteria for economic evaluation. Phone interviews were conducted with professionals (therapists trained and accredited or in the process of becoming accredited DDP practitioners). Three models were developed to represent alternative methods of DDP service delivery. Once appropriate comparators were determined, economic scenarios were constructed. Cost analyses were undertaken from a societal perspective. Finally, appropriate outcome measurement was explored through clinical opinion, literature and further discussions with clinical experts. RESULTS: Three DDP models were constructed: DDP Full-Basic, DDP Home-Based and DDP Long-Term. Two potential comparator interventions were identified and defined as Consultation with Carers and Individual Psychotherapy. Costs of intervention completion per case were estimated to be: £6,700 (DDP Full-Basic), £7,100 (Consultations with Carers), £7,200 (DDP Home-Based), £11,400 (Individual Psychotherapy) and £14,500 (DDP Long-Term). None of the models of service delivery were found to currently measure effectiveness consistently. The Strengths and Difficulties Questionnaire (SDQ) was deemed an appropriate primary outcome measure, however, it does not cover all disorders DDP intends to treat and the SDQ is not a direct measure of health gain. Inclusion of quality of life measurement is required for comprehensive economic analysis. CONCLUSIONS: Economic analysis of DDP in the UK is feasible if vital next steps are taken to measure intervention outcomes consistently, ideally with a quality of life measurement. An economic analysis using the models constructed could determine the potential cost-effectiveness of DDP in the UK and identify the most efficient mode of service delivery.

The feasibility of a randomised controlled trial of Dyadic Developmental Psychotherapy.

BACKGROUND: Maltreated children have significant and complex problems which clinicians find difficult to diagnose and treat. Previous US pilot work suggests that Dyadic Developmental Psychotherapy (DDP) may be effective; however, rigorous evidence from a randomised controlled trial (RCT) is lacking. The purpose of this study is to establish the feasibility of an RCT of DDP by exploring the ways that DDP is operating across different UK sites and the impacts of current practice on the potential set-up of an RCT. METHODS: Qualitative methods (interviews, focus groups and teleconferences) were used to explore trial feasibility with therapists and service managers from teams implementing both DDP and possible control interventions. Data were analysed thematically and related to various aspects of trial design. RESULTS: DDP was commonly regarded as having a particular congruence with the complexity of maltreatment-associated problems and a common operating model of DDP was evident across sites. A single control therapy was harder to establish, however, and it is likely to be a non-specific and context-dependent intervention/s offered within mainstream Child and Adolescent Mental Health Services (CAMHS). Because a 'gold standard' Treatment as Usual (TAU) does not currently exist, randomisation between DDP and TAU (CAMHS) therefore looks feasible and ethical. The nature of family change during DDP was regarded as multi-faceted, non-linear and relationship-based. Assessment tools need to be carefully considered in terms of their ability to capture change that covers both individual child and family-based functioning. CONCLUSIONS: An RCT of DDP is feasible and timely. This study has demonstrated widespread interest, support and engagement regarding an RCT and permissions have been gained from sites that have shown readiness to participate. As maltreated children are among the most vulnerable in society, and as there are currently no treatments with RCT evidence, such a trial would be a major advance in the field.

Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease.

Presenilins (PSs) are part of the gamma-secretase complex that produces the amyloid beta-peptide (Abeta) from its precursor [beta-amyloid precursor protein (betaAPP)]. Mutations in PS that cause familial Alzheimer's disease (FAD) increase Abeta production and trigger p53-dependent cell death. We demonstrate that PS deficiency, catalytically inactive PS mutants, gamma-secretase inhibitors, and betaAPP or amyloid precursor protein-like protein 2 (APLP2) depletion all reduce the expression and activity of p53 and lower the transactivation of its promoter and mRNA expression. p53 expression also is diminished in the brains of PS- or betaAPP-deficient mice. The gamma- and epsilon-secretase-derived amyloid intracellular C-terminal domain (AICD) fragments (AICDC59 and AICDC50, respectively) of betaAPP trigger p53-dependent cell death and increase p53 activity and mRNA. Finally, PS1 mutations enhance p53 activity in human embryonic kidney 293 cells and p53 expression in FAD-affected brains. Thus our study shows that AICDs control p53 at a transcriptional level, in vitro and in vivo, and that FAD mutations increase p53 expression and activity in cells and human brains.

Hypoxia up-regulates prolyl hydroxylase activity: a feedback mechanism that limits HIF-1 responses during reoxygenation.

The mechanism by which hypoxia induces gene transcription is now well established. Hypoxia reduces activity of prolyl hydroxylases (PHD) that hydroxylate specific proline residues in the oxygen-dependent degradation domain (ODD) of hypoxia-inducible factor-1alpha (HIF-1alpha). As a consequence, HIF-1alpha accumulates and promotes hypoxic tolerance by activating gene transcription. This paper identifies the three forms of PHDs in rats and shows that a period of hypoxia selectively increases expression of PHD-2 mRNAs levels. We developed assays for PHD activity that used (i) the peptide-specific conversion of labeled 2-oxoglutarate into succinate and (ii) the binding of the von Hippel-Lindau protein to a glutathione S-transferase-ODD fusion protein. The two assays indicated a low enzymatic activity in normoxic and hypoxic cells and a rapid increase during reoxygenation. We also developed hydroxyproline-specific antibodies that recognized hydroxylated forms of a fusion protein (ODD-green fluorescent protein) that combined the ODD domain of HIF-1alpha and the green fluorescent protein. Using this antibody, we demonstrated that reoxygenation induced a rapid hydroxylation of Pro-564, which was followed by a massive degradation of the proteins. The results suggest that a hypoxic upregulation of PHD (presumably PHD-2) acts as a feedback mechanism to stop hypoxic responses in reoxygenated cells. We propose that proline hydroxylation might play a role in hypoxic preconditioning.