Damage-Associated Molecular Patterns and Systemic Signaling.

Cellular damage inflicted by wounding, pathogen infection, and herbivory releases a variety of host-derived metabolites, degraded structural components, and peptides into the extracellular space that act as alarm signals when perceived by adjacent cells. These so-called damage-associated molecular patterns (DAMPs) function through plasma membrane localized pattern recognition receptors to regulate wound and immune responses. In plants, DAMPs act as elicitors themselves, often inducing immune outputs such as calcium influx, reactive oxygen species generation, defense gene expression, and phytohormone signaling. Consequently, DAMP perception results in a priming effect that enhances resistance against subsequent pathogen infections. Alongside their established function in local tissues, recent evidence supports a critical role of DAMP signaling in generation and/or amplification of mobile signals that induce systemic immune priming. Here, we summarize the identity, signaling, and synergy of proposed and established plant DAMPs, with a focus on those with published roles in systemic signaling.

Perceptions and experiences of control among people living with motor neurone disease: a systematic review and thematic synthesis.

PURPOSE: Current research suggests that feeling a lack of control is common among people living with Motor Neurone Disease (plwMND). This systematic review explores and synthesises evidence about: (1) What factors contribute towards perceptions of control in plwMND (2) How do plwMND attempt to maintain control in their daily lives? METHODS: A systematic search from inception to January 2022 for peer-reviewed journal articles in English reporting qualitative and mixed-method primary studies or reviews of plwMND's perceptions or experiences of control was conducted on CINAHL, MEDLINE, PsycINFO, ASSIA, Embase and AMED. Eligible articles underwent quality appraisal, data extraction and a thematic synthesis was carried out. RESULTS: Twenty publications, 19 primary studies and one review, from nine countries, reporting the views of 578 participants aged from 20 to 90 years were included. Two key analytical themes were identified (1) diagnosis can lead to a disruption of previously held control beliefs (2) plwMND use a range of control strategies to attempt to retain control in their lives. CONCLUSION: This is the first systematic review and qualitative evidence synthesis to reveal the strategies plwMND use to regain control and that control beliefs about health, fate, identity and bodily control are significantly altered by the diagnosis. Implications for rehabilitationOutcome measures for plwMND should consider personal values and preferences as well as objective clinical measurements.plwMND use a range of control strategies which may alter and change over time therefore healthcare professionals may also need to review and adapt treatment decisions over time.The differing viewpoints of healthcare professionals and plwMND should be considered in clinical situations to reduce the potential for conflict.

The Hematology Cancer Patient Experience of "Facing Death" in the Last Year of Life: A Constructivist Grounded Theory Study.

BACKGROUND: For hematology cancer patients, the process of dying is described as "troublesome." Qualitative studies have focused on views of healthcare professionals and caregiver stakeholders. To date, there have been no studies from the patient's perspective on facing death while in the last year of life. OBJECTIVE: The aim of this study was to develop an understanding of the hematology cancer patient's experience of the process of dying in the last year of life. METHODS: The study method was constructivist grounded theory using semistructured interviews, a constant comparison technique, and memoing to collection and analysis of data. The 21 participants were attending a UK cancer center, a cancer unit, or a hospice. RESULTS: This article describes 1 core category within the incurable hematology cancer illness trajectory through 4 subcategories: transitional phase, chronic phase, dying phase, and liminal phase. CONCLUSION: This unique study illustrates that, although life can be prolonged, "facing death" still occurs upon hospitalization and relapse regularly over the illness trajectory. IMPLICATIONS FOR PRACTICE: It is important that clinical practice acknowledges those participants in an incurable illness trajectory while living are focused on avoiding death rather than the ability to cure the disease. Services need to be responsive to the ambiguity of both living and dying by providing holistic management simultaneously, especially after critical episodes of care, to enhance the process of care in the last year of life, and assessment should incorporate the discussion of experiencing life-threatening events.

Effect of financial voucher incentives provided with UK stop smoking services on the cessation of smoking in pregnant women (CPIT III): pragmatic, multicentre, single blinded, phase 3, randomised controlled trial.

OBJECTIVE: To examine effectiveness, cost effectiveness, generalisability, and acceptability of financial incentives for smoking cessation during pregnancy in addition to variously organised UK stop smoking services. DESIGN: Pragmatic, multicentre, single blinded, phase 3, randomised controlled trial (Cessation in Pregnancy Incentives Trial phase 3 (CPIT III)). SETTING: Seven UK stop smoking services provided in primary and secondary care facilities in Scotland, Northern Ireland, and England. PARTICIPANTS: 944 pregnant women (age ≥16 years) who self-reported as being smokers (at least one cigarette in the past week) when asked at first maternity visit, less than 24 weeks' gestation, and notified to the trial team by routine stop smoking services. INTERVENTIONS: Participants in the control group were offered the standard stop smoking services, which includes the offer of counselling by specially trained workers using withdrawal orientated therapy and the offer of free nicotine replacement therapy. The intervention was the offer of usual support from the stop smoking services and the addition of up to £400 ($440; €455) of LoveToShop financial voucher incentives for engaging with current stop smoking services or to stop smoking, or both, during pregnancy. MAIN OUTCOME MEASURES: Self-reported smoking cessation in late pregnancy (between 34 and 38 weeks' gestation) corroborated by saliva cotinine (and anabasine if using nicotine replacement products). Results were adjusted for age, smoking years, index of multiple deprivation, Fagerström score, before or after covid, and recruitment site. Secondary outcomes included point and continuous abstinence six months after expected date of delivery, engagement with stop smoking services, biochemically validated abstinence from smoking at four weeks after stop smoking date, birth weight of baby, cost effectiveness, generalisability documenting formats of stop smoking services, and acceptability to pregnant women and their carers. RESULTS: From 9 January 2018 to 4 April 2020, of 4032 women screened by stop smoking services, 944 people were randomly assigned to the intervention group (n=471) or the control group (n=470). Three people asked for their data to be removed. 126 (27%) of 471 participants stopped smoking from the intervention group and 58 (12%) of 470 from the control group (adjusted odds ratio 2.78 (1.94 to 3.97) P<0.001). Serious adverse events were miscarriages and other expected pregnancy events requiring hospital admission; all serious adverse events were unrelated to the intervention. Most people who stopped smoking from both groups relapsed after their baby was born. CONCLUSIONS: The offer of up to £400 of financial voucher incentives to stop smoking during pregnancy as an addition to current UK stop smoking services is highly effective. This bolt-on intervention supports new guidance from the UK National Institute for Health and Care Excellence, which includes the addition of financial incentives to support pregnant women to stop smoking. Continuing incentives to 12 months after birth is being examined to prevent relapse. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15236311.

Effectiveness and cost-effectiveness of text messages with or without endowment incentives for weight management in men with obesity (Game of Stones): study protocol for a randomised controlled trial.

BACKGROUND: Obesity increases the risk of type 2 diabetes, heart disease, stroke, mobility problems and some cancers, and its prevalence is rising. Men engage less than women in existing weight loss interventions. Game of Stones builds on a successful feasibility study and aims to find out if automated text messages with or without endowment incentives are effective and cost-effective for weight loss at 12 months compared to a waiting list comparator arm in men with obesity. METHODS: A 3-arm, parallel group, assessor-blind superiority randomised controlled trial with process evaluation will recruit 585 adult men with body mass index of 30 kg/m2 or more living in and around three UK centres (Belfast, Bristol, Glasgow), purposively targeting disadvantaged areas. Intervention groups: (i) automated, theory-informed text messages daily for 12 months plus endowment incentives linked to verified weight loss targets at 3, 6 and 12 months; (ii) the same text messages and weight loss assessment protocol; (iii) comparator group: 12 month waiting list, then text messages for 3 months. The primary outcome is percentage weight change at 12 months from baseline. Secondary outcomes at 12 months are as follows: quality of life, wellbeing, mental health, weight stigma, behaviours, satisfaction and confidence. Follow-up includes weight at 24 months. A health economic evaluation will measure cost-effectiveness over the trial and over modelled lifetime: including health service resource-use and quality-adjusted life years. The cost-utility analysis will report incremental cost per quality-adjusted life years gained. Participant and service provider perspectives will be explored via telephone interviews, and exploratory mixed methods process evaluation analyses will focus on mental health, multiple long-term conditions, health inequalities and implementation strategies. DISCUSSION: The trial will report whether text messages (with and without cash incentives) can help men to lose weight over 1 year and maintain this for another year compared to a comparator group; the costs and benefits to the health service; and men's experiences of the interventions. Process analyses with public involvement and service commissioner input will ensure that this open-source digital self-care intervention could be sustainable and scalable by a range of NHS or public services. TRIAL REGISTRATION: ISRCTN 91974895 . Registered on 14/04/2021.

Usual care in a multicentre randomised controlled trial of financial incentives for smoking cessation in pregnancy: qualitative findings from a mixed-methods process evaluation.

OBJECTIVES: Financial incentives are recommended by the UK's National Institute for Health and Care Excellence to aid smoking cessation in pregnancy. However, little is known about how implementation contexts might impact on their effectiveness. Variations in smoking cessation support (usual care) for pregnant women who smoke were examined qualitatively as part of a prospective process evaluation of the Cessation in Pregnancy Incentives Trial (CPIT III). DESIGN: Longitudinal case studies of five CPIT III trial sites informed by realist evaluation. SETTING: A stop smoking service (SSS) serving a maternity hospital constituted each case study, located in three UK countries. PARTICIPANTS: Data collection included semistructured interviews with trial participants (n=22), maternity (n=12) and SSS staff (n=17); and site observations and perspectives recorded in fieldnotes (n=85). RESULTS: Cessation support (usual care) for pregnant women varied in amount, location, staff capacity, flexibility and content across sites. SSS staff capacity was important to avoid gaps in support. Colocation and good working relationships between maternity and SSS professionals enabled prioritisation and reinforced the importance of smoking cessation. Sites with limited use of carbon monoxide (CO) monitoring reduced opportunities to identify smokers while inconsistency around automatic referral processes prevented the offer of cessation support. SSS professionals colocated within antenatal clinics were available to women they could not otherwise reach. Flexibility around location, timing and tailoring of approaches for support, facilitated initial and sustained engagement and reduced the burden on women. CONCLUSIONS: Trial sites faced varied barriers and facilitators to delivering cessation support, reflecting heterogeneity in usual care. If financial incentives are more effective with concurrent smoking cessation support, sites with fewer barriers and more facilitators regarding this support would be expected to have more promising trial outcomes. Future reporting of trial outcomes will assist in understanding incentives' generalisability across a wide range of usual care settings. TRIAL REGISTRATION NUMBER: ISRCTN15236311.

Rescripting-A grounded theory study of the contribution that fathers make to Family-Based Treatment when a young person has anorexia nervosa.

AIM: To present a grounded theory of the contribution that fathers make to family-based treatment when a young person has anorexia nervosa. BACKGROUND: Research indicates a potential to improve outcomes by involving both parents in the treatment of anorexia nervosa. However, fathers are underrepresented both within treatment and research. Family-based treatment requiring the involvement of both parents presents an opportunity to better understand the role of the father in treatment. DESIGN: Classic grounded theory. METHODS: Individual interviews conducted with fifteen fathers involved in family-based treatment. The COREQ checklist was followed. RESULTS: Fathers valued being involved in family-based treatment and felt they had an important contribution to make. The analysis captures the overall contribution that fathers make and the impact of their involvement. Four categories; Being on the Outside, Finding a Way In, Finding a Way to Be and Finding a Way to Let Go and one core category Repositioning were generated from the data. A substantive theory of Rescripting, generated from categories and the core category, describes the way that participating in family-based treatment changes fathers and their role. CONCLUSIONS: Fathers make an important and significant contribution to family-based treatment when a young person has anorexia nervosa. The findings inform clinicians about the importance of including fathers in the treatment of young people with anorexia nervosa. They highlight the importance of incorporating support mechanisms into family-based treatment to harness and maximise the paternal contribution. RELEVANCE TO CLINICAL PRACTICE: Paternal contribution to family-based treatment can be maximised to improve outcomes for young people with anorexia nervosa.

Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. METHODS: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. RESULTS: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. CONCLUSIONS: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. TRIAL REGISTRATION: NCT00977431 (first posted September 15, 2009).

Response to BRAF and MEK1/2 inhibition in a young adult with BRAF V600E mutant epithelioid glioblastoma multiforme: A Case Report and Literature Review.

Epithelioid glioblastoma multiforme (eGBM) is a rare and aggressive variant of glioblastoma multiforme (GBM) that predominantly affects younger patients and can be difficult to distinguish from other gliomas. Data on how patients with eGBM might be best treated are limited, although genomic analyses have shown that almost half of tumours harbour activating BRAF gene mutations. Here we present the case of a young female with BRAF V600E-mutant eGBM who had a prolonged response to targeted therapy with the BRAF and MEK1/2 inhibitors dabrafenib and trametinib. We review current knowledge about eGBM, including the emerging role for BRAF- ± MEK1/2- targeted therapy.

Recruiting men from across the socioeconomic spectrum via GP registers and community outreach to a weight management feasibility randomised controlled trial.

BACKGROUND: Men, particularly those living in disadvantaged areas, are less likely to participate in weight management programmes than women despite similar levels of excess weight. Little is known about how best to recruit men to weight management interventions. This paper describes patient and public involvement in pre-trial decisions relevant to recruitment and aims to report on recruitment to the subsequent men-only weight management feasibility trial, including the: i) acceptability and feasibility of recruitment; and ii) baseline sample characteristics by recruitment strategy. METHODS: Men with BMI ≥30 kg/m2 and/or waist circumference ≥ 40 in. were recruited to the feasibility trial via two strategies; community outreach (venue information stands and word of mouth) and GP letters, targeting disadvantaged areas. Recruitment activities (e.g. letters sent, researcher venue hours) were recorded systematically, and baseline characteristics questionnaire data collated. Qualitative interviews (n = 50) were conducted three months post-recruitment. Analyses and reporting followed a complementary mixed methods approach. RESULTS: 105 men were recruited within four months (community n = 60, GP letter n = 45). Community outreach took 2.3 recruiter hours per participant and GP letters had an opt-in rate of 10.2% (n = 90/879). More men were interested than could be accommodated. Most participants (60%) lived in more disadvantaged areas. Compared to community outreach, men recruited via GP letters were older (mean = 57 vs 48 years); more likely to report an obesity-related co-morbidity (87% vs 44%); and less educated (no formal qualifications, 32% vs 10%, degree educated 11% vs 41%). Recruitment strategies were acceptable, a sensitive approach and trusting relationships with recruiters valued, and the 'catchy' study name drew attention. CONCLUSIONS: Targeted community outreach and GP letters were acceptable strategies that successfully recruited participants to a men-only weight management feasibility trial. Both strategies engaged men from disadvantaged areas, a typically underserved population. Using two recruitment strategies produced samples with different health risk profiles, which could add value to research where either primary or secondary prevention is of interest. Further work is required to examine how these strategies could be implemented and sustained in practice. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03040518 , 2nd February 2017.

Clinical utility of circulating miR-371a-3p for the management of patients with intracranial malignant germ cell tumors.

BACKGROUND: The current biomarkers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) have limited sensitivity/specificity for diagnosing malignant germ cell tumors (GCTs) and "marker-negative" patients require histological confirmation for diagnosis. However, GCTs at intracranial sites are surgically relatively inaccessible and biopsy carries risks. MicroRNAs from the miR-371~373 and miR-302/367 clusters are over-expressed in all malignant GCTs and, in particular, miR-371a-3p shows elevated serum levels at diagnosis for testicular disease. METHODS: Using our robust preamplified qRT-PCR methodology, we quantified miR-371a-3p levels in serum and cerebrospinal fluid (CSF) in a series of 4 representative clinical cases, 3 with intracranial malignant GCT and 1 with Langerhans cell histiocytosis (LCH), compared with appropriate control cases. RESULTS: Serum and/or CSF miR-371a-3p levels distinguished those with intracranial malignant GCTs from LCH and, if known in real time, could have helped clinical management. The benefits would have included (1) the only confirmatory evidence of an intracranial malignant GCT in 1 case, supporting clinical decision making; (2) early detection of intracranial malignant GCT in another, where an elevated CSF miR-371a-3p level preceded the histologically confirmed diagnosis by 2 years; and (3) confirmation of an intracranial malignant GCT relapse with an elevated serum miR-371a-3p level, where serum and CSF AFP and HCG levels were below thresholds for such a diagnosis. CONCLUSIONS: This series highlights the potential for microRNA quantification to assist the noninvasive diagnosis, prognostication, and management for patients with intracranial malignant GCTs. Serum and CSF should be collected routinely as part of future studies to facilitate the extension of these findings to larger patient cohorts.

The influence of contextual factors on healthcare quality improvement initiatives: a realist review.

BACKGROUND: Recognising the influence of context and the context-sensitive nature of quality improvement (QI) interventions is crucial to implementing effective improvements and successfully replicating them in new settings, yet context is still poorly understood. To address this challenge, it is necessary to capture generalisable knowledge, first to understand which aspects of context are most important to QI and why, and secondly, to explore how these factors can be managed to support healthcare improvement, in terms of implementing successful improvement initiatives, achieving sustainability and scaling interventions. The research question was how and why does context influence quality improvement initiatives in healthcare? METHODS: A realist review explored the contextual conditions that influence healthcare improvement. Realist methodology integrates theoretical understanding and stakeholder input with empirical research findings. The review aimed to identify and understand the role of context during the improvement cycle, i.e. planning, implementation, sustainability and transferability; and distil new knowledge to inform the design and development of context-sensitive QI initiatives. We developed a preliminary theory of the influence of context to arrive at a conceptual and theoretical framework. RESULTS: Thirty-five studies were included in the review, demonstrating the interaction of key contextual factors across healthcare system levels during the improvement cycle. An evidence-based explanatory theoretical model is proposed to illustrate the interaction between contextual factors, system levels (macro, meso, micro) and the stages of the improvement journey. Findings indicate that the consideration of these contextual factors would enhance the design and delivery of improvement initiatives, across a range of improvement settings. CONCLUSIONS: This is the first realist review of context in QI and contributes to a deeper understanding of how context influences quality improvement initiatives. The distillation of key contextual factors offers the potential to inform the design and development of context-sensitive interventions to enhance improvement initiatives and address the challenge of spread and sustainability. Future research should explore the application of our conceptual model to enhance improvement-planning processes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017062135.

Outcomes of the First 300 Cases of Transcatheter Aortic Valve Implantation at a High-Volume Australian Private Hospital.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) was first performed in Australia in 2008 with a steady increase in the number of implanting centres from seven in 2008 to 42 in 2018 (24 private and 18 public hospitals). There is limited published data on outcomes from Australian centres and no published data from Australian private hospitals. We describe outcomes of the first 300 cases at Queensland's first TAVI implanting private hospital. METHODS: From July 2015 to August 2018, 300 patients with severe, symptomatic aortic stenosis underwent TAVI at our centre. A heart team assessed all patients as suitable. All patients underwent computed tomography (CT) assessment of valve sizing and peripheral access. RESULTS: Median age was 85 years, 58% male, mean Society of Thoracic Surgeons' score 4.0%, 49% had New York Heart Association Class III/IV, 28% previous coronary artery bypass grafts, 14% peripheral vascular disease and 3.7% renal impairment (creatinine >177 µmol/L). At 30 days mortality was 1%, stroke 1.3%, myocardial infarction (MI) 0.3%, major vascular complication 3.0%, no life-threatening or disabling bleeding and new permanent pacemaker (PPM) requirement was 9.0%. Paravalvular leak was none, trace and mild in 27%, 53% and 20% respectively with 0.3%≥moderate paravalvular leak. At 1 year, mortality was 4.2%, stroke 2.1%, MI 0.3%, no life-threatening bleeding and PPM 11.4%. Lower rates of mortality, stroke, and major vascular complications were observed compared to the well-established TAVI centres in USA and Germany. CONCLUSION: Excellent TAVI clinical outcomes can be achieved in the Australian private hospital setting. Expert heart team assessment and CT guided procedural planning are key to these outcomes.

The smoking cessation in pregnancy incentives trial (CPIT): study protocol for a phase III randomised controlled trial.

BACKGROUND: Eighty per cent of UK women have at least one baby, making pregnancy an opportunity to help women stop smoking before their health is irreparably compromised. Smoking cessation during pregnancy helps protect infants from miscarriage, still birth, low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. UK national guidelines highlight lack of evidence for effectiveness of financial incentives to help pregnant smokers quit. This includes a research recommendation: within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit? METHODS: The Cessation in Pregnancy Incentives Trial (CPIT) III is a pragmatic, 42-month, multi-centre, parallel-group, individually randomised controlled superiority trial of the effect on smoking status of adding to usual Stop Smoking Services (SSS) support, the offer of up to £400 of financial voucher incentives, compared with usual support alone, to quit smoking during pregnancy. Participants (n = 940) are pregnant smokers (age > 16 years, < 24 weeks pregnant, English speaking), who consent via telephone to take part and are willing to be followed-up in late pregnancy and 6 months after birth. The primary outcome is cotinine/anabasine-validated abstinence from smoking in late pregnancy. Secondary outcomes include engagement with SSS, quit rates at 4 weeks from agreed quit date and 6 months after birth, and birth weight. Outcomes will be analysed by intention to treat, and regression models will be used to compare treatment effects on outcomes. A meta-analysis will include data from the feasibility study in Glasgow. An economic evaluation will assess cost-effectiveness from a UK NHS perspective. Process evaluation using a case-study approach will identify opportunities to improve recruitment and learning for future implementation. Research questions include: what is the therapeutic efficacy of incentives; are incentives cost-effective; and what are the potential facilitators and barriers to implementing incentives in different parts of the UK? DISCUSSION: This phase III trial in Scotland, England and Northern Ireland follows a successful phase II trial in Glasgow, UK. The participating sites have diverse SSS that represent most cessation services in the UK and serve demographically varied populations. If found to be acceptable and cost-effective, this trial could demonstrate that financial incentives are effective and transferable to most UK SSS for pregnant women. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN15236311. Registered on 9 October 2017.

Game of Stones: feasibility randomised controlled trial of how to engage men with obesity in text message and incentive interventions for weight loss.

OBJECTIVES: To examine the acceptability and feasibility of narrative text messages with or without financial incentives to support weight loss for men. DESIGN: Individually randomised three-arm feasibility trial with 12 months' follow-up. SETTING: Two sites in Scotland with high levels of disadvantage according to Scottish Index for Multiple Deprivation (SIMD). PARTICIPANTS: Men with obesity (n=105) recruited through community outreach and general practitioner registers. INTERVENTIONS: Participants randomised to: (A) narrative text messages plus financial incentive for 12 months (short message service (SMS)+I), (B) narrative text messages for 12 months (SMS only), or (C) waiting list control. OUTCOMES: Acceptability and feasibility of recruitment, retention, intervention components and trial procedures assessed by analysing quantitative and qualitative data at 3, 6 and 12 months. RESULTS: 105 men were recruited, 60% from more disadvantaged areas (SIMD quintiles 1 or 2). Retention at 12 months was 74%. Fewer SMS+I participants (64%) completed 12-month assessments compared with SMS only (79%) and control (83%). Narrative texts were acceptable to many men, but some reported negative reactions. No evidence emerged that level of disadvantage was related to acceptability of narrative texts. Eleven SMS+I participants (31%) successfully met or partially met weight loss targets. The cost of the incentive per participant was £81.94 (95% CI £34.59 to £129.30). Incentives were acceptable, but improving health was reported as the key motivator for weight loss. All groups lost weight (SMS+I: -2.51 kg (SD=4.94); SMS only: -1.29 kg (SD=5.03); control: -0.86 kg (SD=5.64) at 12 months). CONCLUSIONS: This three-arm weight management feasibility trial recruited and retained men from across the socioeconomic spectrum, with the majority from areas of disadvantage, was broadly acceptable to most participants and feasible to deliver. TRIAL REGISTRATION NUMBER: NCT03040518.

Prevention of suicidal behaviour: Results of a controlled community-based intervention study in four European countries.

The 'European Alliance Against Depression' community-based intervention approach simultaneously targets depression and suicidal behaviour by a multifaceted community based intervention and has been implemented in more than 115 regions worldwide. The two main aims of the European Union funded project "Optimizing Suicide Prevention Programmes and Their Implementation in Europe" were to optimise this approach and to evaluate its implementation and impact. This paper reports on the primary outcome of the intervention (the number of completed and attempted suicides combined as 'suicidal acts') and on results concerning process evaluation analysis. Interventions were implemented in four European cities in Germany, Hungary, Portugal and Ireland, with matched control sites. The intervention comprised activities with predefined minimal intensity at four levels: training of primary care providers, a public awareness campaign, training of community facilitators, support for patients and their relatives. Changes in frequency of suicidal acts with respect to a one-year baseline in the four intervention regions were compared to those in the four control regions (chi-square tests). The decrease in suicidal acts compared to baseline in the intervention regions (-58 cases, -3.26%) did not differ significantly (χ2 = 0.13; p = 0.72) from the decrease in the control regions (-18 cases, -1.40%). However, intervention effects differed between countries (χ2 = 8.59; p = 0.04), with significant effects on suicidal acts in Portugal (χ2 = 4.82; p = 0.03). The interviews and observations explored local circumstances in each site throughout the study. Hypothesised mechanisms of action for successful implementation were observed and drivers for 'added-value' were identified: local partnership working and 'in-kind' contributions; an approach which valued existing partnership strengths; and synergies operating across intervention levels. It can be assumed that significant events during the implementation phase had a certain impact on the observed outcomes. However, this impact was, of course, not proven.

A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma.

PURPOSE: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy ± bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. PATIENTS AND METHODS: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16-06/17) to receive weekly ADI-PEG20 36 mg/m2 intramuscularly plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary endpoints were safety, tolerability, and preliminary estimates of efficacy. RESULTS: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5-20.8) and overall survival was 6.3 months (95% CI, 1.8-9.7). CONCLUSIONS: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls. Additional trials of ADI-PEG20 in HGG are planned.

Uncommon low-grade brain tumors.

The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I-II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management.

Abdominal massage plus advice, compared with advice only, for neurogenic bowel dysfunction in MS: a RCT.

BACKGROUND: Between 50% and 80% of people with multiple sclerosis (PwMS) experience neurogenic bowel dysfunction (NBD) (i.e. constipation and faecal incontinence) that affects quality of life and can lead to hospitalisation. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of abdominal massage plus advice on bowel symptoms on PwMS compared with advice only. A process evaluation investigated the factors that affected the clinical effectiveness and possible implementation of the different treatments. DESIGN: A randomised controlled trial with process evaluation and health economic components. Outcome analysis was undertaken blind. SETTING: The trial took place in 12 UK hospitals. PARTICIPANTS: PwMS who had 'bothersome' NBD. INTERVENTION: Following individualised training, abdominal massage was undertaken daily for 6 weeks (intervention group). Advice on good bowel management as per the Multiple Sclerosis Society advice booklet was provided to both groups. All participants received weekly telephone calls from the research nurse. MAIN OUTCOME MEASURES: The primary outcome was the difference between the intervention and control groups in change in the NBD score from baseline to week 24. Secondary outcomes were measured via a bowel diary, adherence diary, the Constipation Scoring System, patient resource questionnaire and the EuroQol-5 Dimensions, five-level version (EQ-5D-5L). RESULTS: A total of 191 participants were finalised, 189 of whom were randomised (two participants were finalised in error) (control group, n = 99; intervention group, n = 90) and an intention-to-treat analysis was performed. The mean age was 52 years (standard deviation 10.83 years), 81% (n = 154) were female and 11% (n = 21) were wheelchair dependent. Fifteen participants from the intervention group and five from the control group were lost to follow-up. The change in NBD score by week 24 demonstrated no significant difference between groups [mean difference total score -1.64, 95% confidence interval (CI) -3.32 to 0.04; p = 0.0558]; there was a significant difference between groups in the change in the frequency of stool evacuation per week (mean difference 0.62, 95% CI 0.03 to 1.21; p = 0.039) and in the number of times per week that participants felt that they emptied their bowels completely (mean difference 1.08, 95% CI 0.41 to 1.76; p = 0.002), in favour of the intervention group. Of participant interviewees, 75% reported benefits, for example less difficulty passing stool, more complete evacuations, less bloated, improved appetite, and 85% continued with the massage. A cost-utility analysis conducted from a NHS and patient cost perspective found in the imputed sample with bootstrapping a mean incremental outcome effect of the intervention relative to usual care of -0.002 quality-adjusted life-years (QALYs) (95% CI -0.029 to 0.027 QALYs). In the same imputed sample with bootstrapping, the mean incremental cost effect of the intervention relative to usual care was £56.50 (95% CI -£372.62 to £415.68). No adverse events were reported. Limitations include unequal randomisation, dropout and the possibility of ineffective massage technique. CONCLUSION: The increment in the primary outcome favoured the intervention group, but it was small and not statistically significant. The economic analysis identified that the intervention was dominated by the control group. Given the small improvement in the primary outcome, but not in terms of QALYs, a low-cost version of the intervention might be considered worthwhile by some patients. FUTURE WORK: Research is required to establish possible mechanisms of action and modes of massage delivery. TRIAL REGISTRATION: Current Controlled Trials ISRCTN85007023 and NCT03166007. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 58. See the NIHR Journals Library website for further project information.