TREATMENT SWITCHING: STATISTICAL AND DECISION-MAKING CHALLENGES AND APPROACHES.

OBJECTIVES: Treatment switching refers to the situation in a randomized controlled trial where patients switch from their randomly assigned treatment onto an alternative. Often, switching is from the control group onto the experimental treatment. In this instance, a standard intention-to-treat analysis does not identify the true comparative effectiveness of the treatments under investigation. We aim to describe statistical methods for adjusting for treatment switching in a comprehensible way for nonstatisticians, and to summarize views on these methods expressed by stakeholders at the 2014 Adelaide International Workshop on Treatment Switching in Clinical Trials. METHODS: We describe three statistical methods used to adjust for treatment switching: marginal structural models, two-stage adjustment, and rank preserving structural failure time models. We draw upon discussion heard at the Adelaide International Workshop to explore the views of stakeholders on the acceptability of these methods. RESULTS: Stakeholders noted that adjustment methods are based on assumptions, the validity of which may often be questionable. There was disagreement on the acceptability of adjustment methods, but consensus that when these are used, they should be justified rigorously. The utility of adjustment methods depends upon the decision being made and the processes used by the decision-maker. CONCLUSIONS: Treatment switching makes estimating the true comparative effect of a new treatment challenging. However, many decision-makers have reservations with adjustment methods. These, and how they affect the utility of adjustment methods, require further exploration. Further technical work is required to develop adjustment methods to meet real world needs, to enhance their acceptability to decision-makers.

Identification of priorities for improvement of medication safety in primary care: a PRIORITIZE study.

BACKGROUND: Medication error is a frequent, harmful and costly patient safety incident. Research to date has mostly focused on medication errors in hospitals. In this study, we aimed to identify the main causes of, and solutions to, medication error in primary care. METHODS: We used a novel priority-setting method for identifying and ranking patient safety problems and solutions called PRIORITIZE. We invited 500 North West London primary care clinicians to complete an open-ended questionnaire to identify three main problems and solutions relating to medication error in primary care. 113 clinicians submitted responses, which we thematically synthesized into a composite list of 48 distinct problems and 45 solutions. A group of 57 clinicians randomly selected from the initial cohort scored these and an overall ranking was derived. The agreement between the clinicians' scores was presented using the average expert agreement (AEA). The study was conducted between September 2013 and November 2014. RESULTS: The top three problems were incomplete reconciliation of medication during patient 'hand-overs', inadequate patient education about their medication use and poor discharge summaries. The highest ranked solutions included development of a standardized discharge summary template, reduction of unnecessary prescribing, and minimisation of polypharmacy. Overall, better communication between the healthcare provider and patient, quality assurance approaches during medication prescribing and monitoring, and patient education on how to use their medication were considered the top priorities. The highest ranked suggestions received the strongest agreement among the clinicians, i.e. the highest AEA score. CONCLUSIONS: Clinicians identified a range of suggestions for better medication management, quality assurance procedures and patient education. According to clinicians, medication errors can be largely prevented with feasible and affordable interventions. PRIORITIZE is a new, convenient, systematic, and replicable method, and merits further exploration with a view to becoming a part of a routine preventative patient safety monitoring mechanism.

An Ion-Pair Induced Intermediate Complex Captured in Class D Carbapenemase Reveals Chloride Ion as a Janus Effector Modulating Activity.

Antibiotic-resistant Enterobacterales that produce oxacillinase (OXA)-48-like Class D ß-lactamases are often linked to increased clinical mortality. Though the catalytic mechanism of OXA-48 is known, the molecular origin of its biphasic kinetics has been elusive. We here identify selective chloride binding rather than decarbamylation of the carbamylated lysine as the source of biphasic kinetics, utilizing isothermal titration calorimetry (ITC) to monitor the complete reaction course with the OXA-48 variant having a chemically stable N-acetyl lysine. Further structural investigation enables us to capture an unprecedented inactive acyl intermediate wedged in place by a halide ion paired with a conserved active site arginine. Supported by mutagenesis and mathematical simulation, we identify chloride as a "Janus effector" that operates by allosteric activation of the burst phase and by inhibition of the steady state in kinetic assays of ß-lactams. We show that chloride-induced biphasic kinetics directly affects antibiotic efficacy and facilitates the differentiation of clinical isolates encoding Class D from Class A and B carbapenemases. As chloride is present in laboratory and clinical procedures, our discovery greatly expands the roles of chloride in modulating enzyme catalysis and highlights its potential impact on the pharmacokinetics and efficacy of antibiotics during in vivo treatment.

A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo.

The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP - a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.

Mixed methods study of medication-related decision support alerts experienced during electronic prescribing for inpatients at an English hospital.

OBJECTIVES: Electronic prescribing and medication administration systems are being introduced in many hospitals worldwide, with varying degrees of clinical decision support including pop-up alerts. Previous research suggests that prescribers override a high proportion of alerts, but little research has been carried out in the UK. Our objective was to explore rates of alert overriding in different prescribing situations and prescribers' perceptions around the use of decision support alerts in a UK hospital. METHODS: We conducted a mixed methods study on three cardiology wards, directly observing medical and non-medical prescribers' alert override rates during both ward round and non-ward round prescribing; observations were followed by semi-structured interviews with prescribers, which were then transcribed and analysed thematically. RESULTS: Overall, 69% of 199 observed alerts were overridden. Alerts experienced during ward rounds were significantly more likely to be overridden than those outside of ward rounds (80% of 56 vs 51% of 63; p=0.001, Χ2 test). While respondents acknowledged that alerts could be useful, several also described negative unintended consequences. Many were of the view that usefulness of alerts was limited if the alert was reminding them to do something they would do anyway, or suggesting something they did not feel was relevant. Findings suggest that targeting, timing and additional features of alerts are critical factors in determining whether they are acted on or overridden. CONCLUSION: The majority of alerts were overridden. Alerts may be less likely to be overridden if they are built into the prescribing workflow.

Clinical efficacy, cost analysis and patient acceptability of outpatient parenteral antibiotic therapy (OPAT): a decade of Sheffield (UK) OPAT service.

Outpatient parenteral antimicrobial therapy (OPAT) has evolved relatively slowly in the UK. This study describes the OPAT service based in a large UK teaching hospital in Sheffield, and examines the clinical efficacy, patient acceptability and costs saved over a 10-year period. Data on 3812 episodes of OPAT administered between January 2006 and January 2016 were retrieved from a prospectively maintained electronic database. This study compared the real costs of the OPAT service with estimated costs of conventional inpatient care for these patient episodes, and analysed patient feedback questionnaires that were administered randomly between January 2014 and January 2015. A wide range of infections were managed during the 10-year period. Skin and soft tissue infections accounted for 57% of OPAT episodes. The total number of bed-days saved was 49,854. A successful outcome (cure or improvement) was found in 3357 (88%) episodes. Re-admission occurred in 265 (7%) episodes. The rates of healthcare-associated infections were low: 15 intravenous-line-related infections were recorded (0.3 per 1000 OPAT patient-days). Patient acceptance and satisfaction with OPAT were high. OPAT cost 15%, 39%, 40% and 44% of inpatient costs for an infectious diseases unit, national average costs, other departments (non-infectious diseases unit), and the minimum national average costs for each diagnostic category, respectively. This study shows that OPAT is safe, clinically efficacious and acceptable for treating a wide range of infections with high levels of patient satisfaction and substantial cost savings.

Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy.

Trametinib, a selective inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression-free survival compared with chemotherapy in patients with BRAF V600E/K mutation-positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival (OS) advantage of trametinib. Our purpose was to estimate the switching-adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank-preserving structural failure time model, inverse probability of censoring weights, and a two-stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent-to-treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [HR], 0.72; 95% CI, 0.52-0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first-line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation-positive advanced melanoma or MM. Adjusting for switching resulted in lower HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method.

Exploring the Current Landscape of Intravenous Infusion Practices and Errors (ECLIPSE): protocol for a mixed-methods observational study.

INTRODUCTION: Intravenous medication is essential for many hospital inpatients. However, providing intravenous therapy is complex and errors are common. 'Smart pumps' incorporating dose error reduction software have been widely advocated to reduce error. However, little is known about their effect on patient safety, how they are used or their likely impact. This study will explore the landscape of intravenous medication infusion practices and errors in English hospitals and how smart pumps may relate to the prevalence of medication administration errors. METHODS AND ANALYSIS: This is a mixed-methods study involving an observational quantitative point prevalence study to determine the frequency and types of errors that occur in the infusion of intravenous medication, and qualitative interviews with hospital staff to better understand infusion practices and the contexts in which errors occur. The study will involve 5 clinical areas (critical care, general medicine, general surgery, paediatrics and oncology), across 14 purposively sampled acute hospitals and 2 paediatric hospitals to cover a range of intravenous infusion practices. Data collectors will compare each infusion running at the time of data collection against the patient's medication orders to identify any discrepancies. The potential clinical importance of errors will be assessed. Quantitative data will be analysed descriptively; interviews will be analysed using thematic analysis. ETHICS AND DISSEMINATION: Ethical approval has been obtained from an NHS Research Ethics Committee (14/SC/0290); local approvals will be sought from each participating organisation. Findings will be published in peer-reviewed journals and presented at conferences for academic and health professional audiences. Results will also be fed back to participating organisations to inform local policy, training and procurement. Aggregated findings will inform the debate on costs and benefits of the NHS investing in smart pump technology, and what other changes may need to be made to ensure effectiveness of such an investment.

Intracellular signalling and cancer: complex pathways lead to multiple targets.

Normal cells proliferate, die and differentiate as and when they should for the proper functioning of any particular tissue type. These processes are governed by a complex series of intracellular pathways that have many internal checkpoints and safety nets. These ensuring a fine, but tight, balance on overall tissue growth and distribution. A series of key aberrations, resulting in the disruption of these intracellular pathways, can lead to the development of a malignancy. The nature of these alterations is often not only tumour-specific, but also different between individuals with the same tumour type. As a result, these pathways have to be carefully dissected and functionally assessed to identify valid targets with therapeutic potential in a wide range of tumour types.

In vitro modelling of Alzheimer's disease: degeneration and cell death induced by viral delivery of amyloid and tau.

With increasing life expectancy, Alzheimer's disease (AD) and other dementias pose an increasing and as yet unresolved health problem. A variety of cellular models of AD has helped to decipher some key aspects of amyloid and tau related degeneration. The initial approach of extracellular applications of synthetic peptides has now been replaced by the introduction of amyloid precursor protein (APP) and tau genes. In the present study adenoviral transductions were exploited for gene delivery into primary rat hippocampal and dorsal root ganglion (DRG) cultures to enable comparative and mechanistic studies at the cellular level and subsequent drug testing. Time lapse experiments revealed a different pattern of cell death: apoptotic-like for APP whereas tau positive cells joined and formed clusters. Mutated human APP or tau expression caused accelerated neuronal damage and cell death (cf. EGFP: -50% for APP at 5 days; -40% for tau at 3 days). This reduction in viability was preceded by decreased excitability, monitored via responses to depolarising KCl-challenges in Ca(2+) imaging experiments. Additionally, both transgenes reduced neurite outgrowth in DRG neurones. Treatment studies confirmed that APP induced-damage can be ameliorated by ß- and γ-secretase inhibitors (providing protection to 60-100% of control levels), clioquinol (80%) and lithium (100%); while anti-aggregation treatments were beneficial for tau-induced damage (60-90% recovery towards controls). Interestingly, caffeine was the most promising drug candidate for therapeutic intervention with high efficacy in both APP (77%) and tau-induced models (72% recovery). Overall, these cellular models offer advantages for mechanistic studies and target identification in AD and related disorders.

A women's worker in court: a more appropriate service for women defendants with mental health issues?

AIMS: Court liaison services aim to reduce mental illness in prison through early treatment and/or diversion into care of defendants negotiating their court proceedings. However, liaison services may inadvertently contribute to gender inequalities in mental health in the prison system because women often do not access liaison services. This is attributed to services failing to recognize that women have different needs from men. To address this, it is essential that the needs of women in contact with the criminal justice system (CJS) are clearly articulated. However, there is a dearth of research that considers women's needs at this stage of their journey through the CJS. This paper aims to identify these needs before women enter prison. It does so through an analysis of a pilot Women's Support Service based at a magistrates' court, a response to concerns that women were not accessing the local liaison service. METHODS: Proformas were completed by a women's specialist worker for 86 women defendants assessed over four months. Information was collected on characteristics including education, domestic violence, accommodation, physical and mental health. This specialist worker recorded the range of needs identified by defendants at assessment and the services to which women were referred. RESULTS: Access to the Women's Support Service is high, with only 11.3% of women refusing to use the service. Women attending have high levels of physical and mental health issues. Their mental health issues have not being addressed prior to accessing the service. Women often come from single households and environments high in domestic abuse. Women have multiple needs related to benefits, finance, housing, domestic abuse, education and career guidance. These are more frequent than those that explicitly link to mental health. The women's worker providing the service referred women to 68 services from a wide variety of statutory and voluntary organizations. CONCLUSIONS: The Women's Support Service is accessed by a higher number of women, many more than access the local liaison service. It is suggested that this is due to their multiple and gender-specific needs being adequately addressed by the former service and the organizations to which they are referred. Mental health needs may also be secondary to other more basic needs, which makes the generic service provided by the Women's Support Service more appropriate than a liaison service that deals with mental health support alone.

iASPP inhibition: increased options in targeting the p53 family for cancer therapy.

Strategies to induce p53 for cancer therapy offer appeal but many tumors harbor inactivating p53 mutations. One way to address this situation may be to activate the p53-related protein p73, which functions similarly, but unlike p53, is rarely lost or mutated in cancer. Along these lines, a recent study reports that a p53-derived peptide that targets iASPP-a common negative regulator of p53 family members--can effectively trigger tumor cell death by a p73-dependent mechanism. These findings promote further study of iASPP targeting as a therapeutic strategy to activate p73.

Targeting the p53 family for cancer therapy: 'big brother' joins the fight.

Inactivation of p53-mediated signaling plays a major role in both the genesis and therapy resistance of human cancer. Nearly all tumors contain mutations in p53 itself or have perturbations in the p53 pathway. Since there is clear evidence that many tumor cells are more likely to die in response to wild-type p53 activation or restoration than are their normal counterparts, there has been considerable interest in the development of small molecules that target p53 for therapeutic gain. These include compounds that either revert mutant p53 back to its wild-type conformation or compounds which interfere with the binding to, or the ubiquitylation of, p53 by MDM2. In both cases, however, the efficacy of the strategy depends on the presence of either mutant or wild-type p53 respectively thereby limiting their application to specific tumor settings. As a result, recent strategies have turned to the p53 family member, p73, which like p53 is a potent inducer of death, but in contrast is rarely lost or mutated in tumors. We discuss here all these different strategies and in particular focus on the discovery of an apoptotic peptide which targets not just p73, but potentially all p53 family members to cause tumor cell death.

Molecular mechanisms underlying dexamethasone inhibition of iNOS expression and activity in C6 glioma cells.

The synthetic glucocorticoid dexamethasone is routinely used to stabilize patients with malignant gliomas. One putative target for glucocorticoid action is inducible nitric oxide synthase (iNOS), which is produced by the tumor cells as well as the host immune cells. In this study, we characterize the stimulatory effects of lipopolysaccharide (LPS) and the cytokine, tumor necrosis factor-alpha (TNFalpha), as well as the inhibitory effect of glucocorticoids, on iNOS gene expression and activity in C6 glioma cells cultured in vitro. LPS significantly increased iNOS mRNA expression, peaking at 6 h, while nitrite formation increased with time up to 72 h. Although TNFalpha alone induced neither iNOS mRNA expression nor nitrite formation, it significantly potentiated the effect of LPS on both. iNOS activity induced by LPS with or without TNFalpha was dose-dependently inhibited by dexamethasone, reaching a maximum of approximately 83% inhibition. This was completely reversed by the addition of RU38486, an antagonist of glucocorticoid receptors (GR). Dexamethasone inhibited iNOS mRNA expression; however, the maximum inhibition obtained was only 10%. These results suggest that as for induction of iNOS activity in C6 cells in vitro, the stimulatory effect of LPS is mainly due to an action at the transcriptional level. TNFalpha does not have intrinsic inducing activity, but has potentiating effects at the transcriptional and possibly at the posttranscriptional levels in the presence of LPS. The inhibitory effect of dexamethasone is GR-mediated and is mainly due to action at the posttranscriptional level.