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

Vacuum-UV negative photoion spectroscopy of CH3F, CH3Cl and CH3Br

Using tunable vacuum-UV radiation from a synchrotron, negative ions are detected by quadrupolar mass spectrometry following photoexcitation of three gaseous halogenated methanes CH$_3$X (X = F,Cl,Br). The anions X$^-$, H$^-$, CX$^-$, CHX$^-$ and CH$_2$X$^-$ are observed, and their ion yields recorded in the range 8-35 eV. The anions show a linear dependence of signal with pressure, showing that they arise from unimolecular ion-pair dissociation, generically described as AB + h$v$ $\rightarrow$ A$^-$ + B$^+$ (+ neutrals). Absolute cross sections for ion-pair formation are obtained by calibrating the signal intensities with those of F$^-$ from both SF$_6$ and CF$_4$. The cross sections for formation of X$^-$ + CH$_3$$^+$ are much greater than for formation of CH$_2$X$^-$ + H$^+$. In common with many quadrupoles, the spectra of $m$/$z$ 1 (H$^-$) anions show contributions from all anions, and only for CH$_3$Br is it possible to perform the necessary subtraction to obtain the true H$^-$ spectrum. The anion cross sections are normalised to vacuum-UV absorption cross sections to obtain quantum yields for their production. The appearance energies of X$^-$ and CH$_2$X$^-$ are used to calculate upper limits to 298 K bond dissociation energies for D$^o$ (H$_3$C-X) and D$^o$ (XH$_2$C-H) which are consistent with literature values. The spectra suggest that most of the anions are formed indirectly by crossing of Rydberg states of the parent molecule onto an ion-pair continuum. The one exception is the lowest-energy peak of F$^-$ from CH$_3$F at 13.4 eV, where its width and lack of structure suggest it may correspond to a direct ion-pair transition

Extrapolation of survival curves using standard parametric models and flexible parametric spline models: comparisons in large registry cohorts with advanced cancer

Background: It is often important to extrapolate survival estimates beyond the limited follow-up times of clinical trials. Extrapolated survival estimates can be highly sensitive to model choice; thus, appropriate model selection is crucial. Flexible parametric spline models have been suggested as an alternative to standard parametric models; however, their ability to extrapolate is not well understood. Aim: To determine how well standard parametric and flexible parametric spline models predict survival when fitted to registry cohorts with artificially right-censored follow-up times. Methods: Adults with advanced breast, colorectal, small cell lung, non–small cell lung, or pancreatic cancer with a potential follow-up time of 10 y were selected from the SEER 1973–2015 registry data set. Patients were classified into 15 cohorts by cancer and age group at diagnosis (18–59, 60–69, 70+ y). Follow-up times for each cohort were right censored at 20%, 35%, and 50% survival. Standard parametric models (exponential, Weibull, Gompertz, log-logistic, log-normal, generalized gamma) and spline models (proportional hazards, proportional odds, normal/probit) were fitted to the 10-y data set and the 3 right-censored data sets. Predicted 10-y restricted mean survival time and percentage surviving at 10 y were compared with the observed values. Results: Across all data sets, the spline odds and spline normal models most frequently gave accurate predictions of 10-y survival outcomes. Visually, spline models tended to demonstrate better fit to the observed hazard functions than standard parametric models, both in the censored and 10-y data. Conclusions: In these cohorts, where there was little uncertainty in the observed data, the spline models performed well when extrapolating beyond the observed data. Spline models should be routinely included in the set of models that are fitted when extrapolating cancer survival data

Randomised controlled trial and health economic evaluation of the impact of diagnostic testing for influenza, respiratory syncytial virus and Streptococcus pneumoniae infection on the management of acute admissions in the elderly and high-risk 18- to 64-year-olds

Please cite the published version which is available via the DOI link in this record.Western industrialised nations face a large increase in the number of older people. People over the age of 60 years account for almost half of the 16.8 million hospital admissions in England from 2009 to 2010. During 2009-10, respiratory infections accounted for approximately 1 in 30 hospital admissions and 1 in 20 of the 51.5 million bed-days.HTA ProgrammeNational Institute for Health Research (NIHR

Repelling neoliberal world-making? How the ageing–dementia relation is reassembling the social

Growing old ‘badly’ is stigmatizing, a truism that is enrolled into contemporary agendas for the biomedicalization of ageing. Among the many discourses that emphasize ageing as the root cause of later life illnesses, dementia is currently promoted as an epidemic and such hyperbole serves to legitimate its increasing biomedicalization. The new stigma however is no longer contained to simply having dementia, it is failing to prevent it. Anti-ageing cultures of consumption, alongside a proliferation of cultural depictions of the ageing–dementia relation, seem to be refiguring dementia as a future to be worked on to eliminate it from our everyday life. The article unpacks this complexity for how the ageing–dementia relation is being reassembled in biopolitics in ways that enact it as something that can be transformed and managed. Bringing together Bauman’s theories of how cultural communities cope with the otherness of the other with theories of the rationale for the making of monsters – such as the figure of the abject older person with dementia – the article suggests that those older body-persons that personify the ageing–dementia relation, depicted in film and television for example, threaten the modes of ordering underpinning contemporary lives. This is not just because they intimate loss of mind, or because they are disruptive, but because they do not perform what it is to be ‘response-able’ and postpone frailty through managing self and risk

Challenges in valuing and paying for combination regimens in oncology: reporting the perspectives of a multi‐stakeholder, international workshop

Background It is increasingly common for two or more treatments for cancer to be combined as a single regimen. Determining value and appropriate payment for such regimens can be challenging. This study discusses these challenges, and possible solutions. Methods Stakeholders from around the world attended a 2-day workshop, supported by a background paper. This study captures key outcomes from the discussion, but is not a consensus statement. Results Workshop attendees agreed that combining on-patent treatments can result in affordability and value for money challenges that delay or deny patient access to clinically effective treatments in many health systems. Options for addressing these challenges include: (i) Increasing the value of combination therapies through improved clinical development; (ii) Willingness to pay more for combinations than for single drugs offering similar benefit, or; (iii) Aligning the cost of constituent therapies with their value within a regimen. Workshop attendees felt that (i) and (iii) merited further discussion, whereas (ii) was unlikely to be justifiable. Views differed on the feasibility of (i). Key to (iii) would be systems allowing different prices to apply to different uses of a drug. Conclusions Common ground was identified on immediate actions to improve access to combination regimens. These include an exploration of the legal challenges associated with price negotiations, and ensuring that pricing systems can support implementation of negotiated prices for specific uses. Improvements to clinical development and trial design should be pursued in the medium and longer term

Developing accessible, pictorial versions of health-related quality of life instruments suitable for economic evaluation: a report of preliminary studies conducted in Canada and the United Kingdom

A key component of the current framework for economic evaluation is the measurement and valuation of health outcomes using generic preference-based health-related quality of life (HRQoL) instruments. In 2015, a research synthesis reported the absence of conceptual and empirical research regarding the appropriateness of current preference-based instruments for people with aphasia – a disorder affecting the use and understanding of language – and suggested the development and validation of an accessible, pictorial variant could be an appropriate direction for further research. This paper describes the respective rationale and development process for each of three preliminary studies that have been undertaken to develop pictorial variants of two widely-used preference-based HRQoL instruments (EQ-5D-3L and EQ-5D-5L). The paper also proposes next steps for this program of research, drawing on the lessons learned from the preliminary work and the demand for a pictorial preference-based instrument in the research community. Guidance for the use of the preliminary, pictorial instruments is also provided

The effectiveness and satisfaction of web-based physiotherapy in people with spinal cord injury: a pilot randomised controlled trial

Study Design: Pilot randomised controlled trial. Objectives: The aims of this study were to evaluate the effectiveness and participant satisfaction of web-based physiotherapy for people with Spinal Cord Injury (SCI). Setting: Community patients of a national spinal injury unit in a university teaching hospital, Scotland, UK. Methods: Twenty-four participants were recruited and randomised to receive eight weeks of web-based physiotherapy (intervention), twice per week, or usual care (control). Individual exercise programmes were prescribed based upon participant’s abilities. The intervention was delivered via a website (www.webbasedphysio.com) and monitored and progressed remotely by the physiotherapist. Results: Participants logged on to the website an average of 1.4±0.8 times per week. Between-group differences, although not significant were more pronounced for the 6 minute walk test. Participants were positive about using web-based physiotherapy and stated they would be happy to use it again and would recommend it to others. Overall it was rated as either good or excellent. Conclusions: Web-based physiotherapy was feasible and acceptable for people with SCI. Participants achieved good compliance with the intervention, rated the programme highly and beneficial for health and well-being at various states post injury. The results of this study warrant further work with a more homogenous sample

Cenobamate, a Sodium Channel Inhibitor and Positive Allosteric Modulator of GABAA Ion Channels, for Partial Onset Seizures in Adults: A Comprehensive Review and Clinical Implications

Medical management of epilepsy seeks to eliminate or to reduce the frequency of seizures, help patients maintain a normal lifestyle, and maintain psychosocial and occupational activities, while avoiding the negative side effects of long-term treatment. Current FDA approved drugs have been shown to have similar efficacy; however, they all share a commonality of having side effects that have the potential to significantly reduce a patient’s quality of life. Cenobamate, a newly-FDA approved drug used to treat partial-onset seizures in adult patients, has demonstrated promise in that it works on two proposed mechanisms that are commonly associated with epilepsy. Cenobamate acts as a positive allosteric modulator of the GABAA ion channels and is effective in reducing repetitive neuronal firing by inhibition of voltage-gated sodium channels, although the complete mechanism of action is currently unknown. The efficacy of Cenobamate with its low toxicity and adverse drug reaction profile emphasizes the need to further evaluate antiepileptic therapies containing sulfamoylphenyl and/or carbamate moieties in their chemical structure. Recent studies have found more patients to be seizure free during the maintenance period when compared to placebo. The most common side effects reported in with Cenobamate are somnolence, dizziness, headache, nausea, and fatigue. There are currently ongoing phase III studies looking to further evaluate the long-term benefits of Cenobamate and investigate adverse events