Tumor Susceptibility Gene 101 (TSG101) Is a Novel Binding-Partner for the Class II Rab11-FIPs

The Rab11-FIPs (Rab11-family interacting proteins; henceforth, FIPs) are a family of Rab11a/Rab11b/Rab25 GTPase effector proteins implicated in an assortment of intracellular trafficking processes. Through proteomic screening, we have identified TSG101 (tumor susceptibility gene 101), a component of the ESCRT-I (endosomal sorting complex required for transport) complex, as a novel FIP4-binding protein, which we find can also bind FIP3. We show that α-helical coiled-coil regions of both TSG101 and FIP4 mediate the interaction with the cognate protein, and that point mutations in the coiled-coil regions of both TSG101 and FIP4 abrogate the interaction. We find that expression of TSG101 and FIP4 mutants cause cytokinesis defects, but that the TSG101-FIP4 interaction is not required for localisation of TSG101 to the midbody/Flemming body during abscission. Together, these data suggest functional overlap between Rab11-controlled processes and components of the ESCRT pathway

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Exploring internet needs for the management of adolescent chronic pain: developing digital interventions in context

Chronic pain in children and adolescents is recognised internationally as a long-term health condition, which can have a substantial impact on the quality of life of young people and their families, as well as representing a substantial economic burden across healthcare sectors. The prevalence of chronic pain in children and adolescents varies across diagnoses, age groups and genders. Primary chronic pain is often idiopathic and secondary conditions range from chronic headaches to musculoskeletal pain. The overarching aim of the current thesis is to lay the groundwork for developing a novel online intervention for the management of adolescent chronic pain. The thesis firstly outlines the problem of paediatric and adolescent chronic pain and describes current evidence-based best practices for chronic pain management. This is followed by an outline of methodological approaches to online health intervention development, including the Medical Research Council guidance for developing complex health interventions and the Person-Based Approach to developing digital health interventions. An explanation of how these approaches were used in the thesis, and rationale underpinning the chosen methods, is provided. Theoretical models pertaining to the maintenance and management of chronic pain are outlined, followed by the presentation of three papers. Paper 1 presents a review and content analysis of online interventions that have been developed for the management of paediatric and adolescent chronic pain. Findings highlight that, whilst CBT-based interventions have been largely successful, most interventions do not encompass multidisciplinary pain management. The review identifies that a UK-centric online intervention for paediatric chronic pain has not yet been developed. Paper 2 presents a needs-assessment survey of adolescents with chronic pain and their parents. This study explores needs and preferences of this population for a novel intervention. Findings draw attention to the integration of internet and social media use by young people for pain management purposes. A qualitative content analysis of survey responses reveals that adolescents would endorse a new online pain management intervention. Paper 3 presents a qualitative interview study with adolescents with chronic pain, which further explores the context of internet and social media use in young people. An inductive thematic analysis presents four themes: ‘Trustworthy information, or experiences?’, ‘Diagnostic labels in a digital world’, ‘The online chronic pain community’, and ‘A mind and body approach to self-management.’ The general discussion presents guiding principles that intervention developers and chronic pain specialists may use when creating or adapting online interventions

Chronic pain prevalence and quality of life in survivors of paediatric cancer: A systematic review

Background: As survival rates of paediatric cancers continue to improve, there is a growing need for research into survivorship, particularly in children and adolescents. Aims: This study will a) systematically review current literature on the prevalence of chronic pain (CP) in survivors of childhood cancer; b) review the relationship between pain prevalence in paediatric cancer survivors and health-related quality of life (HRQOL), and c) compare CP and HRQOL between adult survivors of paediatric cancer (18+) and survivors within the paediatric age range (0-18). Methods: A systematic review will be conducted in accordance with PRISMA guidelines. Studies will be identified via a search of Medline, PsychINFO, Web of Science, CINAHL, PubMed, Scopus, Cochrane Library, Google Scholar and OpenGrey databases from inception of the databases to November 2017. We will include all study formats reporting any point or period prevalence estimates, from a survivor sample (i.e., not currently receiving cancer treatment), diagnosed with cancer between 0 and 18 years and experiencing chronic pain i.e., defined as pain in one or more body locations, lasting for a period of 3 months or longer. The articles will be appraised using a risk of bias tool developed specifically for prevalence studies (Hoy et al., 2012). Results & Conclusion: The studies will be synthesised and pooled prevalence estimates will be calculated for chronic pain in adult and paediatric survivors of childhood cancer. The results will be discussed in light of relevant findings, and recommendations for further research will be made regarding the clinical care of survivors

Trusting in the online ‘community’: An interview study exploring internet use in young people with chronic pain

BACKGROUND: Chronic pain in young people is prevalent in the UK. Young people are digital natives, yet there has not been any online intervention developed in a UK context to help them manage chronic pain. Key to understanding the context in which young people engage with online interventions is better understanding their internet use for chronic pain management. The overarching aim of this study was to explore young peoples’ experiences of searching for information about chronic pain using the internet. This included experiences of using search engines (e.g. Google), health information websites (e.g. the National Health Service [NHS] website) and social media (e.g. Facebook and Instagram). METHODS: Semi-structured interviews were conducted with young people aged 16–24-years (n = 24), online, via Microsoft (MS) Teams. The study was advertised online and via patient partner charities. Interview data was analysed using reflexive thematic analysis. RESULTS: Participants presented with a variety of chronic pain conditions, including joint hypermobility syndrome (n = 6), chronic headache and/or migraine (n = 4) and fibromyalgia (n = 3). Four themes were generated: ‘Trustworthy information, or experiences?’, ‘Diagnostic labels in a digital world’, ‘The online chronic pain community’ and ‘A mind and body approach to self-management’. Young people trust advice from others in their online community and having a diagnostic label help them find relevant pain management strategies and support networks online. CONCLUSIONS: This study is the first qualitative exploration of internet use in UK-based young people with chronic pain. Findings highlight the importance of considering internet use when developing new online interventions for young people with pain and that internet use, particularly social media use, is an important psychosocial consideration in pain management. Young people should be encouraged to verify practical pain management techniques found online with their doctor and be empowered in the safe use of appropriate psychology-based self-management resources

Qualtrics survey data extraction (SPSS and Excel) for "Online paediatric chronic pain management: assessing the needs of UK adolescents and parents, using a cross-sectional survey"

Dataset to support article in British Journal of Pain &quot;Online paediatric chronic pain management: assessing the needs of UK adolescents and parents, using a cross-sectional survey&quot; https://doi.org/10.1177/2049463720940341. Survey data extraction relating to published survey investigating internet needs for adolescents with chronic pain. UK and non-UK participants included in SPSS extraction. Qualitative free text data (used for content analysis) summarised in Excel file.</span