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

Measuring the mass of a sterile neutrino with a very short baseline reactor experiment

An analysis of the world's neutrino oscillation data, including sterile neutrinos, (M. Sorel, C. M. Conrad, and M. H. Shaevitz, Phys. Rev. D 70, 073004) found a peak in the allowed region at a mass-squared difference $\Delta m^2 \cong 0.9$ eV$^2$. We trace its origin to harmonic oscillations in the electron survival probability $P_{ee}$ as a function of L/E, the ratio of baseline to neutrino energy, as measured in the near detector of the Bugey experiment. We find a second occurrence for $\Delta m^2 \cong 1.9$ eV$^2$. We point out that the phenomenon of harmonic oscillations of $P_{ee}$ as a function of L/E, as seen in the Bugey experiment, can be used to measure the mass-squared difference associated with a sterile neutrino in the range from a fraction of an eV$^2$ to several eV$^2$ (compatible with that indicated by the LSND experiment), as well as measure the amount of electron-sterile neutrino mixing. We observe that the experiment is independent, to lowest order, of the size of the reactor and suggest the possibility of a small reactor with a detector sitting at a very short baseline.Comment: 4 pages, 2 figure

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

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

Computerised speech and language therapy or attention control added to usual care for people with long-term post-stroke aphasia : the Big CACTUS three-arm RCT

Background: People with aphasia may improve their communication with speech and language therapy many months/years after stroke. However, NHS speech and language therapy reduces in availability over time post stroke. Objective: This trial evaluated the clinical effectiveness and cost-effectiveness of self-managed computerised speech and language therapy to provide additional therapy. Design: A pragmatic, superiority, single-blind, parallel-group, individually randomised (stratified block randomisation, stratified by word-finding severity and site) adjunct trial. Setting: Twenty-one UK NHS speech and language therapy departments. Participants: People with post-stroke aphasia (diagnosed by a speech and language therapist) with long-standing (> 4 months) word-finding difficulties. Interventions: The groups were (1) usual care; (2) daily self-managed computerised word-finding therapy tailored by speech and language therapists and supported by volunteers/speech and language therapy assistants for 6 months plus usual care (computerised speech and language therapy); and (3) activity/attention control (completion of puzzles and receipt of telephone calls from a researcher for 6 months) plus usual care. Main outcome measures: Co-primary outcomes – change in ability to find treated words of personal relevance in a bespoke naming test (impairment) and change in functional communication in conversation rated on the activity scale of the Therapy Outcome Measures (activity) 6 months after randomisation. A key secondary outcome was participant-rated perception of communication and quality of life using the Communication Outcomes After Stroke questionnaire at 6 months. Outcomes were assessed by speech and language therapists using standardised procedures. Cost-effectiveness was estimated using treatment costs and an accessible EuroQol-5 Dimensions, five-level version, measuring quality-adjusted life-years. Results: A total of 818 patients were assessed for eligibility and 278 participants were randomised between October 2014 and August 2016. A total of 240 participants (86 usual care, 83 computerised speech and language therapy, 71 attention control) contributed to modified intention-to-treat analysis at 6 months. The mean improvements in word-finding were 1.1% (standard deviation 11.2%) for usual care, 16.4% (standard deviation 15.3%) for computerised speech and language therapy and 2.4% (standard deviation 8.8%) for attention control. Computerised speech and language therapy improved word-finding 16.2% more than usual care did (95% confidence interval 12.7% to 19.6%; p < 0.0001) and 14.4% more than attention control did (95% confidence interval 10.8% to 18.1%). Most of this effect was maintained at 12 months (n = 219); the mean differences in change in word-finding score were 12.7% (95% confidence interval 8.7% to 16.7%) higher in the computerised speech and language therapy group (n = 74) than in the usual-care group (n = 84) and 9.3% (95% confidence interval 4.8% to 13.7%) higher in the computerised speech and language therapy group than in the attention control group (n = 61). Computerised speech and language therapy did not show significant improvements on the Therapy Outcome Measures or Communication Outcomes After Stroke scale compared with usual care or attention control. Primary cost-effectiveness analysis estimated an incremental cost per participant of £732.73 (95% credible interval £674.23 to £798.05). The incremental quality-adjusted life-year gain was 0.017 for computerised speech and language therapy compared with usual care, but its direction was uncertain (95% credible interval –0.05 to 0.10), resulting in an incremental cost-effectiveness ratio of £42,686 per quality-adjusted life-year gained. For mild and moderate word-finding difficulty subgroups, incremental cost-effectiveness ratios were £22,371 and £28,898 per quality-adjusted life-year gained, respectively, for computerised speech and language therapy compared with usual care. Limitations: This trial excluded non-English-language speakers, the accessible EuroQol-5 Dimensions, five-level version, was not validated and the measurement of attention control fidelity was limited. Conclusions: Computerised speech and language therapy enabled additional self-managed speech and language therapy, contributing to significant improvement in finding personally relevant words (as specifically targeted by computerised speech and language therapy) long term post stroke. Gains did not lead to improvements in conversation or quality of life. Cost-effectiveness is uncertain owing to uncertainty around the quality-adjusted life-year gain, but computerised speech and language therapy may be more cost-effective for participants with mild and moderate word-finding difficulties. Exploring ways of helping people with aphasia to use new words in functional communication contexts is a priority. Trial registration: Current Controlled Trials ISRCTN68798818

Process evaluation of appreciative inquiry to translate pain management evidence into pediatric nursing practice

Background Appreciative inquiry (AI) is an innovative knowledge translation (KT) intervention that is compatible with the Promoting Action on Research in Health Services (PARiHS) framework. This study explored the innovative use of AI as a theoretically based KT intervention applied to a clinical issue in an inpatient pediatric care setting. The implementation of AI was explored in terms of its acceptability, fidelity, and feasibility as a KT intervention in pain management. Methods A mixed-methods case study design was used. The case was a surgical unit in a pediatric academic-affiliated hospital. The sample consisted of nurses in leadership positions and staff nurses interested in the study. Data on the AI intervention implementation were collected by digitally recording the AI sessions, maintaining logs, and conducting individual semistructured interviews. Data were analysed using qualitative and quantitative content analyses and descriptive statistics. Findings were triangulated in the discussion. Results Three nurse leaders and nine staff members participated in the study. Participants were generally satisfied with the intervention, which consisted of four 3-hour, interactive AI sessions delivered over two weeks to promote change based on positive examples of pain management in the unit and staff implementation of an action plan. The AI sessions were delivered with high fidelity and 11 of 12 participants attended all four sessions, where they developed an action plan to enhance evidence-based pain assessment documentation. Participants labeled AI a 'refreshing approach to change' because it was positive, democratic, and built on existing practices. Several barriers affected their implementation of the action plan, including a context of change overload, logistics, busyness, and a lack of organised follow-up. Conclusions Results of this case study supported the acceptability, fidelity, and feasibility of AI as a KT intervention in pain management. The AI intervention requires minor refinements (e.g., incorporating continued follow-up meetings) to enhance its clinical utility and sustainability. The implementation process and effectiveness of the modified AI intervention require evaluation in a larger multisite study

The driver landscape of sporadic chordoma

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma

Development of a ParticipACTION App–Based Intervention for Improving Postsecondary Students’ 24-Hour Movement Guideline Behaviors: Protocol for the Application of Intervention Mapping

Background:The Canadian 24-Hour Movement Guidelines for adults provide specific recommendations for levels of physical activity, sedentary behavior, and sleep (ie, the movement behaviors) required for optimal health. Performance of the movement behaviors is associated with improved mental well-being. However, most postsecondary students do not meet the movement behavior recommendations within the Canadian 24-Hour Movement Guidelines and experience increased stress and declining well-being, suggesting the need for an intervention targeting students’ movement behaviors.Objective:We aimed to develop and implement a theory-informed intervention intended to improve the movement behaviors and mental well-being of first-year postsecondary students.Methods:The Intervention Mapping protocol was applied in the development and implementation of the intervention. Intervention Mapping entailed performing a needs assessment, determining the intervention outcomes, selecting theory- and evidence-based change methods and applications, preparing and producing intervention plans and materials, developing the implementation plan, and finally developing an evaluation plan. The Theoretical Domains Framework and the Behavior Change Wheel were also used in conjunction with the Intervention Mapping protocol to ensure a solid theoretical basis for the intervention. This protocol led to the development and implementation of a 6-week, theory-informed ParticipACTION app–based intervention aimed at helping first-year postsecondary students improve their movement behaviors and mental well-being. The developed app content provided students with information on each of the movement behaviors and behavioral strategies (ie, goal setting, action planning, monitoring, and coping planning). The use of Intervention Mapping allowed for the continuous involvement of various multidisciplinary partners and end users, ensuring that the intervention design and implementation was appropriate for the target audience. The feasibility, acceptability, and potential impact of the intervention will be examined in a subsequent proof-of-concept study at 2 Canadian university campuses.Results:Participant recruitment occurred during September 2021, and the intervention was conducted from October to December 2021. The deadline for completion of the postintervention questionnaire by participants was mid-December 2021. The analysis of data examining the feasibility, acceptability, and potential impact of the intervention began in January 2022, with the publication of the proof-of-concept evaluation expected in 2023.Conclusions:Intervention Mapping with the Theoretical Domains Framework and Behavior Change Wheel was a useful approach to combine evidence and theoretical concepts to guide the design and implementation of a ParticipACTION app–based intervention targeting postsecondary students’ movement behaviors and mental well-being. This process may serve as an example for other researchers developing multiple behavior change app–based interventions. Should the forthcoming evaluation demonstrate the intervention’s acceptability, feasibility, and potential impact, the intervention may provide a scalable method of improving postsecondary students’ movement behaviors and mental well-being