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Background: Different dementia support roles exist but evidence is lacking on which aspects are best, for whom, and in what circumstances, and on their associated costs and benefits. Phase 1 of the Dementia PersonAlised Care Team programme (D-PACT) developed a post-diagnostic primary care-based intervention for people with dementia and their carers and assessed the feasibility of a trial., Aim: Phase 2 of the programme aims to 1) refine the programme theory on how, when, and for whom the intervention works; and 2) evaluate its value and impact., Design & Setting: A realist longitudinal mixed-methods evaluation will be conducted in urban, rural, and coastal areas across South West and North West England where low-income or ethnic minority populations (for example, South Asian) are represented. Design was informed by patient, public, and professional stakeholder input and phase 1 findings., Method: High-volume qualitative and quantitative data will be collected longitudinally from people with dementia, carers, and practitioners. Analyses will comprise the following: 1) realist longitudinal case studies; 2) conversation analysis of recorded interactions; 3) statistical analyses of outcome and experience questionnaires; 4a) health economic analysis examining costs of delivery; and 4b) realist economic analysis of high-cost events and 'near misses'. All findings will be synthesised using a joint display table, evidence appraisal tool, triangulation, and stakeholder co-analysis., Conclusion: The realist evaluation will describe how, why, and for whom the intervention does or does not lead to change over time. It will also demonstrate how a non-randomised design can be more appropriate for complex interventions with similar questions or populations., (Copyright © 2023, The Authors.)

Aims: For smokers unmotivated to quit, we assessed the effectiveness and cost-effectiveness of behavioural support to reduce smoking and increase physical activity on prolonged abstinence and related outcomes., Design: A multi-centred pragmatic two-arm parallel randomised controlled trial., Setting: Primary care and the community across four United Kingdom sites., Participants: Nine hundred and fifteen adult smokers (55% female, 85% White), recruited via primary and secondary care and the community, who wished to reduce their smoking but not quit., Interventions: Participants were randomised to support as usual (SAU) (n = 458) versus multi-component community-based behavioural support (n = 457), involving up to eight weekly person-centred face-to-face or phone sessions with additional 6-week support for those wishing to quit., Measurements: Ideally, cessation follows smoking reduction so the primary pre-defined outcome was biochemically verified 6-month prolonged abstinence (from 3-9 months, with a secondary endpoint also considering abstinence between 9 and 15 months). Secondary outcomes included biochemically verified 12-month prolonged abstinence and point prevalent biochemically verified and self-reported abstinence, quit attempts, number of cigarettes smoked, pharmacological aids used, SF12, EQ-5D and moderate-to-vigorous physical activity (MVPA) at 3 and 9 months. Intervention costs were assessed for a cost-effectiveness analysis., Findings: Assuming missing data at follow-up implied continued smoking, nine (2.0%) intervention participants and four (0.9%) SAU participants achieved the primary outcome (adjusted odds ratio, 2.30; 95% confidence interval [CI] = 0.70-7.56, P = 0.169). At 3 and 9 months, the proportions self-reporting reducing cigarettes smoked from baseline by ≥50%, for intervention versus SAU, were 18.9% versus 10.5% (P = 0.009) and 14.4% versus 10% (P = 0.044), respectively. Mean difference in weekly MVPA at 3 months was 81.6 minutes in favour of the intervention group (95% CI = 28.75, 134.47: P = 0.003), but there was no significant difference at 9 months (23.70, 95% CI = -33.07, 80.47: P = 0.143). Changes in MVPA did not mediate changes in smoking outcomes. The intervention cost was £239.18 per person, with no evidence of cost-effectiveness., Conclusions: For United Kingdom smokers wanting to reduce but not quit smoking, behavioural support to reduce smoking and increase physical activity improved some short-term smoking cessation and reduction outcomes and moderate-to-vigorous physical activity, but had no long-term effects on smoking cessation or physical activity., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: The e-coachER trial aimed to determine whether adding web-based behavioural support to exercise referral schemes (ERS) increased long-term device-measured physical activity (PA) for patients with chronic conditions, compared to ERS alone, within a randomised controlled trial. This study explores the mechanisms of action of the e-coachER intervention using measures of the behaviour change processes integral to the intervention's logic model., Methods: Four hundred fifty adults with obesity, diabetes, hypertension, osteoarthritis or history of depression referred to an ERS were recruited in Plymouth, Birmingham and Glasgow. The e-coachER intervention comprising 7-Steps to Health was aligned with Self-Determination Theory and mapped against evidence-based behaviour change techniques (BCTs). Participants completed questionnaires at 0, 4, and 12 months to assess PA and self-reported offline engagement with core BCTs in day-to-day life (including action planning and self-monitoring) and beliefs relating to PA (including perceived importance, confidence, competence, autonomy and support). We compared groups at 4 and 12 months, controlling for baseline measures and other covariates. Mediation analysis using the product of coefficients method was used to determine if changes in process variables mediated intervention effects on moderate to vigorous physical activity (MVPA) recorded by accelerometer and self-report at 4- and 12-months., Results: The internal reliability (Cronbach's alpha) for all multi-item scales was > 0.77. At 4-months, those randomised to e-coachER reported higher levels of PA beliefs relating to importance (1.01, 95% confidence interval (CI): 0.42 to 1.61, p = 0.001), confidence (1.28, 95% CI: 0.57 to 1.98, p < 0.001), competence (1.61, 95% CI: .68 to 2.54, p = 0.001), availability of support (0.77, 95% CI: 0.07 to 1.48, p = 0.031), use of action planning (1.54, 95% CI: 0.23 to 2.85, p = 0.021) and use of self-monitoring (0.76, 95% CI: 0.19 to 1.32, p = 0.009) compared to ERS alone. There were no intervention effects on autonomous beliefs or perceived frequency of support, compared to ERS alone. At the 12-month follow-up, participants belief in the importance of PA was the only process measure to remain significantly higher in the e-coachER group when compared to ERS alone (0.75, 95% CI: 0.05 to 1.45). Intervention effects on perceived importance (2.52, 95% CI: 0.45 to 5.39), action planning (1.56, 95% CI: 0.10 to 3.54) and self-monitoring (1.92, 95% CI: 0.21 to 4.33) at 4-months significantly mediated change in accelerometer measured MVPA at 12-months (recorded in ≥ 10-min bouts)., Conclusions: e-coachER led to some short-term changes in most process outcomes. Some of these processes also appeared to mediate e-coachER effects on changes in accelerometer measured MVPA. Further work should be carried out to understand how best to design and implement theoretically underpinned web-based physical activity promotion interventions within ERS., Trial Registration: ISRCTN, ISRCTN15644451 . Registered 12 February 2015., (© 2022. The Author(s).)

Background: Approximately 15 million people in the UK live with obesity, around 5 million of whom have severe obesity (body mass index (BMI) ≥35kg/m 2 ). Having severe obesity markedly compromises health, well-being and quality of life, and substantially reduces life expectancy. These adverse outcomes are prevented or ameliorated by weight loss, for which sustained behavioural change is the cornerstone of treatment. Although NHS specialist 'Tier 3' Weight Management Services (T3WMS) support people with severe obesity, using individual and group-based treatment, the current evidence on optimal intervention design and outcomes is limited. Due to heterogeneity of severe obesity, there is a need to tailor treatment to address individual needs. Despite this heterogeneity, there are good reasons to suspect that a structured group-based behavioural intervention may be more effective and cost-effective for the treatment of severe obesity compared to usual care. The aims of this study are to test the feasibility of establishing and delivering a multi-centre randomised controlled clinical trial to compare a group-based behavioural intervention versus usual care in people with severe obesity., Methods: This feasibility randomised controlled study is a partially clustered multi-centre trial of PROGROUP (a novel group-based behavioural intervention) versus usual care. Adults ≥18 years of age who have been newly referred to and accepted by NHS T3WMS will be eligible if they have a BMI ≥40, or ≥35 kg/m 2 with comorbidity, are suitable for group-based care and are willing to be randomised. Exclusion criteria are participation in another weight management study, planned bariatric surgery during the trial, and unwillingness or inability to attend group sessions. Outcome assessors will be blinded to treatment allocation and success of blinding will be evaluated. Clinical measures will be collected at baseline, 6 and 12 months post-randomisation. Secondary outcome measures will be self-reported and collected remotely. Process and economic evaluations will be conducted., Discussion: This randomised feasibility study has been designed to test all the required research procedures and additionally explore three key issues; the feasibility of implementing a complex trial at participating NHS T3WMS, training the multidisciplinary healthcare teams in a standard intervention, and the acceptability of a group intervention for these particularly complex patients., Trial Registration: ISRCTN number 22088800., (© 2022. The Author(s).)

Abstract: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications., Competing Interests: D.F.M. has received research support for the clinical study of ketamine in depression and past travel expenses for program and research development from the National Network of Depression Centers. He has research support from Janssen at present. He has past research funding from Neuronetics and St. Jude Medical in the past 10 years; Mustafa Husain has received support from the National Institutes of Health (NIH), National Institute of Mental Health (NIMH), National Institute on Aging (NIA), National Institute of Neurological Disorders and Stroke, Brain Initiative, and the Stanley Medical Research Institute. He has received industry grant support from Abbott, Cyberonics, Neuronetics, Brainsway, and NeoSync; William M. McDonald is a member of the American Psychiatric Association Council on Research representing electroconvulsive therapy and neuromodulation therapies. He is compensated as the chair of the Data Safety and Monitoring Board (DSBM) for an NIA multicenter study. He is on the Board of Skyland Trail and 3Keys. He is a paid consultant for Signant Health. He has received past funding from the Stanley Foundation, Soterix, Neuronetics, NeoSync, and Cervel Neurotherapeutics. He has an endowed chair funded by the JB Fuqua Foundation. S. Selek received internal funding from the University of Texas Health Science Center at Houston McGovern Medical School, Louis A. Faillace Department of Psychiatry. S.M.M. has received research funding from the NIH and is a consultant for the Pearson Assessment. E.A. has received funding from the NIA. J.H.W. is a consultant or has equity interest at Mindstreet Inc; American Psychiatric Publishing, Inc; Guilford Press; and Simon and Schuster Book Royalties. He has received grant support from the Agency for Healthcare Research and Quality. T.S. has received funding from the NIH and the Foundation of Hope for Research and Treatment of Mental Illness. W.I. has received funding from the NIMH T32 Psychiatric Epidemiology Training Program (T32MH014592-41). I.M.R. was supported by the NIMH (R01 MH121542) and The Jager Family Foundation. P.P.Z., M.M., R.W.S., S.K.C., K.R., B.R.C., S.J.S., P.D.P., R.D.W., N.F.R., M.T.B., M.C., K.G., A.F., N.T.T., O.F.P., M.J.D., K.K., S. Sampson, and Y.S. have no conflicts of interest or financial disclosures to report., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Children with cerebral palsy (CP) frequently undertake physiotherapy programmes to improve walking and balance. They often require adult support to exercise in a functional position. A novel interactive exercise trainer has been devised to enable children to exercise with against resistance in a functional position, but its efficacy has yet to be proved. A novel protocol has been developed to determine whether a randomised controlled trial (RCT) is feasible., Aim: To establish whether it is feasible to conduct an RCT to assess the effectiveness of a 10-week physiotherapy intervention using an interactive trainer in children with CP., Methods and Analysis: This study is multicentre randomised controlled feasibility trial with an embedded qualitative study. Forty children with CP, Gross Motor Function Classification System (GMFCS) I-III will be recruited from community paediatric physiotherapy caseloads. Participants will be randomised to 10 weeks of training with the interactive training device or to usual physiotherapy care. The mediolateral motion of the centre of mass estimate and Paediatric Balance Scale will be explored as potential primary outcomes measures, tested at baseline, 10 weeks and follow-up at 20 weeks. The views of child participants, their parents and physiotherapists will be gained through e-diaries and qualitative interviews.Feasibility will be determined by examining recruitment and retention rates, completeness of, adherence to the intervention, appropriateness of outcome measures and effectiveness of blinding. Results will be reported in accordance to Consolidated Standards of Reporting Trials (CONSORT) guidelines., Ethics and Dissemination: Physiotherapists, children and parents have informed trial design and information leaflets. Results will be disseminated via publications, conferences and to families. This study has approval from North of Scotland Research Ethics Committee (20/NS/0018)., Trial Registration Number: ISRCTN80878394., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Invasive Aspergillosis (IA), typically caused by the fungus Aspergillus fumigatus , is a leading cause of morbidity and mortality in immunocompromised patients. IA remains a significant burden in haematology patients, despite improvements in the diagnosis and treatment of Aspergillus infection. Diagnosing IA is challenging, requiring multiple factors to classify patients into possible, probable and proven IA cohorts. Given the low incidence of IA, using negative results as exclusion criteria is optimal. However, frequent false positives and severe IA mortality rates in haematology patients have led to the empirical use of toxic, drug-interactive and often ineffective anti-fungal therapeutics. Improvements in IA diagnosis are needed to reduce unnecessary anti-fungal therapy. Early IA diagnosis is vital for positive patient outcomes; therefore, a pre-emptive approach is required. In this study, we examined the sequence and expression of four C-type Lectin-like receptors (Dectin-1, Dectin-2, Mincle, Mcl) from 42 haematology patients and investigated each patient's anti- Aspergillus immune response (IL-6, TNF). Correlation analysis revealed novel IA disease risk factors which we used to develop a pre-emptive patient stratification protocol to identify haematopoietic stem cell transplant patients at high and low risk of developing IA. This stratification protocol has the potential to enhance the identification of high-risk patients whilst reducing unnecessary treatment, minimizing the development of anti-fungal resistance, and prioritising primary disease treatment for low-risk patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Griffiths, White, Thompson, da Fonseca, Pickering, Ingram, Wilson, Barnes, Taylor and Orr.)

Immunocompromised patients are highly susceptible to invasive aspergillosis. Herein, we identified a homozygous deletion mutation (507 del C) resulting in a frameshift (N170I) and early stop codon in the fungal binding Dectin-2 receptor, in an immunocompromised patient. The mutated form of Dectin-2 was weakly expressed, did not form clusters at/near the cell surface and was functionally defective. Peripheral blood mononuclear cells from this patient were unable to mount a cytokine (tumor necrosis factor, interleukin 6) response to Aspergillus fumigatus, and this first identified Dectin-2-deficient patient died of complications of invasive aspergillosis., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Study Objective: Epistaxis is a common emergency department (ED) presentation and, if simple first aid measures fail, can lead to a need for anterior nasal packing. Tranexamic acid is an agent that contributes to blood clot stability. The aim of this study is to investigate the effectiveness of topical intranasal tranexamic acid in adult patients presenting to the ED with persistent epistaxis, and whether it reduces the need for anterior nasal packing., Methods: From May 5, 2017, to March 31, 2019, a double-blind, placebo-controlled, multicenter, 1:1, randomized controlled trial was conducted across 26 EDs in the United Kingdom. Participants with spontaneous epistaxis, persisting after simple first aid and the application of a topical vasoconstrictor, were randomly allocated to receive topical tranexamic acid or placebo. The primary outcome was the need for anterior nasal packing of any kind during the index ED attendance. Secondary outcome measures included hospital admission, need for blood transfusion, recurrent epistaxis, and any thrombotic events requiring any hospital reattendance within 1 week., Results: The study sample consisted of 496 participants with spontaneous epistaxis, persisting after simple first aid and application of a topical vasoconstrictor. In total, 211 participants (42.5%) received anterior nasal packing during the index ED attendance, including 111 of 254 (43.7%) in the tranexamic acid group versus 100 of 242 (41.3%) in the placebo group. The difference was not statistically significant (odds ratio 1.107; 95% confidence interval 0.769 to 1.594; P=.59). Furthermore, there were no statistically significant differences between tranexamic acid and placebo for any of the secondary outcome measures., Conclusion: In patients presenting to an ED with atraumatic epistaxis that is uncontrolled with simple first aid measures, topical tranexamic acid applied in the bleeding nostril on a cotton wool dental roll is no more effective than placebo at controlling bleeding and reducing the need for anterior nasal packing., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Prior research has shown that onset or exacerbation of OCD is associated with menstruation, pregnancy, and the post-partum period. However, the underlying cause is unclear. The goal of this study was to assess whether pregnancy and birth complications were associated with OCD symptoms exacerbation, among women with established OCD. Two-hundred and five (n=205) women with OCD retrospectively reported information on their physical and mental health during their first pregnancy. Over a third of the sample (34%) reported an exacerbation in their OCD symptoms. History of pregnancy and birth complications in the first pregnancy were similar between women who did and did not experience symptom exacerbation, with the exception of gestational diabetes, which was significantly more common among women who experienced exacerbation (7% vs 1%, p=0.03). In a multivariable logistic regression model, gestational diabetes remained significantly associated with exacerbation of OCD symptoms (OR=8.44 [95% CI 1.37-77.27]; p=0.03), even after adjusting for maternal age, OCD severity and treatment, premenstrual OCD symptom increase, stress during pregnancy, and major depression or anxiety disorder diagnosis during pregnancy. We discuss potential explanations for this link. These findings should be treated as hypothesis-generating and need to be replicated in a larger, prospective study., Competing Interests: Conflict of Interest Declarations of interest: none

Chimeric antigen receptor (CAR)-expressing T cells now offer an effective treatment option for people with previously refractory B cell malignancies and are under development for a wide range of other tumours. However, neurological toxicity is a common complication of CAR-T cell therapy, seen in over 50% of recipients in some cohorts. Since 2018, the term immune effector cell-associated neurotoxicity syndrome (ICANS) has been used to describe and grade neurotoxicity seen after CAR-T cells and other similar therapies. ICANS following CAR-T therapy is usually self-limiting but can necessitate admission to the intensive care unit and is rarely fatal. As CAR-T therapies enter routine clinical practice, it is important for neurologists to be aware of the nature of neurological complications. Here, we summarise the clinical manifestations, mechanisms, investigations and recommended treatment of CAR-T-related neurotoxicity, focusing on the licensed CD19 products.

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

This study of patients with acute myelogenous leukemia (AML) age ≥60 years analyzed the association between patients' performance indices-Hematopoietic Stem Cell Transplantation Comorbidity Index (HCT-CI), Karnofsky Performance Score (KPS), and European Society for Blood and Marrow Transplantation (EBMT) risk score-before undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and quality of life (QoL), quantified using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), in the first year after allo-HSCT. Over a period of 7 years, 48 evaluable patients underwent reduced-intensity conditioning allo-HSCT. The median patient age was 65 years (range, 60 to 74 years), with 2-year and 5-year overall survival (OS) of 65.8% and 52.3%, respectively. A significant improvement across all QoL scores was observed over the 12 months post-HSCT. An HCT-CI of 0 was associated with improved general QoL (FACT-G) score at 6 months compared with patients with an HCT-CI of 1 to 2 (P= .032). At 12 months post-HSCT, a pretransplantation HCT-CI ≥3 was correlated with lower QoL scores across the domains (symptom-related QoL [FACT-TOI], P= .036; FACT-G, P= .05; BMT-related QoL [FACT-BMT], P= .036). A pretransplantation KPS score of 100 versus 80 to 90 was predictive of improved QoL at 6 months post-HSCT (FACT-TOI, P = .009; FACT-G, P= .001; FACT-BMT, P= .002) but not at 1 year post-HSCT. We demonstrate that KPS and HCT-CI can predict QoL in the early post-transplantation period, with a favorable overall survival in a selected cohort of AML patients age ≥60 years., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Major Depressive Disorder (MDD) is one of the most common mental illnesses and a leading cause of disability worldwide. Electronic Health Records (EHR) allow researchers to conduct unprecedented large-scale observational studies investigating MDD, its disease development and its interaction with other health outcomes. While there exist methods to classify patients as clear cases or controls, given specific data requirements, there are presently no simple, generalizable, and validated methods to classify an entire patient population into varying groups of depression likelihood and severity., Methods: We have tested a simple, pragmatic electronic phenotype algorithm that classifies patients into one of five mutually exclusive, ordinal groups, varying in depression phenotype. Using data from an integrated health system on 278,026 patients from a 10-year study period we have tested the convergent validity of these constructs using measures of external validation, including patterns of psychiatric prescriptions, symptom severity, indicators of suicidality, comorbidity, mortality, health care utilization, and polygenic risk scores for MDD., Results: We found consistent patterns of increasing morbidity and/or adverse outcomes across the five groups, providing evidence for convergent validity., Limitations: The study population is from a single rural integrated health system which is predominantly white, possibly limiting its generalizability., Conclusion: Our study provides initial evidence that a simple algorithm, generalizable to most EHR data sets, provides categories with meaningful face and convergent validity that can be used for stratification of an entire patient population., Competing Interests: Conflict of Interest The authors declare that they have no conflict of interest.

Purpose: To investigate the effect of Tai Chi exercise on postural balance among people with dementia (PWD) and the feasibility of a definitive trial on falls prevention., Patients and Methods: Dyads, comprising community-dwelling PWD and their informal carer (N=85), were randomised to usual care (n=43) or usual care plus weekly Tai Chi classes and home practice for 20 weeks (n=42). The primary outcome was the timed up and go test. All outcomes for PWD and their carers were assessed six months post-baseline, except for falls, which were collected prospectively over the six-month follow-up period., Results: For PWD, there was no significant difference at follow-up on the timed up and go test (mean difference [MD] = 0.82, 95% confidence interval [CI] = -2.17, 3.81). At follow-up, PWD in the Tai Chi group had significantly higher quality of life (MD = 0.051, 95% CI = 0.002, 0.100, standardised effect size [ES] = 0.51) and a significantly lower rate of falls (rate ratio = 0.35, 95% CI =0.15, 0.81), which was no longer significant when an outlier was removed. Carers in the Tai Chi group at follow-up were significantly worse on the timed up and go test (MD = 1.83, 95% CI = 0.12, 3.53, ES = 0.61). The remaining secondary outcomes were not significant. No serious adverse events were related to participation in Tai Chi., Conclusion: With refinement, this Tai Chi intervention has potential to reduce the incidence of falls and improve quality of life among community-dwelling PWD [Trial registration: NCT02864056]., Competing Interests: Dr Samuel R Nyman, Dr Wendy Ingram, Dr Jeanette Sanders, Professor Peter W Thomas, Dr Sarah Thomas, Professor James Raftery, and Dr Yolanda Barrado-Martín report the above grant from the National Institute for Health Research (NIHR) for the conduct of the study. Ms Iram Bibi was funded by Bournemouth University. The authors report no other conflicts of interest in this work., (© 2019 Nyman et al.)

Electroconvulsive therapy (ECT) is an effective and rapid treatment for severe depression, however predictors of therapeutic outcomes remain insufficiently understood. Ictal duration and postictal suppression are two outcomes that may be correlated with patient response, yet patient and treatment variables which may influence these outcomes have not been thoroughly explored. We collected ECT stimulus metrics, EEG parameters, patient demographics, primary diagnosis, and anesthesia type for retrospective ECTs. Univariate and multivariate mixed-effects linear regression models were used to identify variables associated with ictal duration and postictal suppression index. For both outcomes, multivariate models which included all variables resulted in the best fit, reflecting the complex influences of a variety of factors on the ictal response. These results are an important step forward in elucidating patterns in retrospective ECT clinical data which may lead to new clinical knowledge of modifiable factors to optimize ECT treatment outcomes.

Background: Falls are a public health issue for the older adult population and more so for people with dementia (PWD). Compared with their cognitively intact peers, PWD are at higher risk of falls and injurious falls. This randomised controlled trial aims to test the clinical and cost effectiveness of Tai Chi to improve postural balance among community-dwelling PWD and to assess the feasibility of conducting a larger definitive trial to reduce the incidence of falls among PWD., Methods: A 3-centre parallel group randomised controlled trial with embedded process evaluation. One hundred and fifty community-dwelling dyads of a person with dementia and their informal carer will be recruited and assessed at baseline and at six-month follow-up. Dyads will be randomised in a 1:1 ratio to either usual care or usual care plus a Tai Chi intervention for 20 weeks. The Tai Chi intervention will consist of weekly classes (45 min' Tai Chi plus up to 45 min for informal discussion, with up to 10 dyads per class) and home-based exercises (20 min per day to be facilitated by the carer). Home practice of Tai Chi will be supported by the use of behaviour change techniques with the Tai Chi instructor at a home visit in week 3-4 of the intervention (action planning, coping planning, self-monitoring, and alarm clock reminder) and at the end of each class (feedback on home practice). The primary outcome is dynamic balance measured using the Timed Up and Go test, coinciding with the end of the 20-week intervention phase for participants in the Tai Chi arm. Secondary outcomes for PWD include functional balance, static balance, fear of falling, global cognitive functioning, visual-spatial cognitive functioning, quality of life, and falls. Secondary outcomes for carers include dynamic balance, static balance, quality of life, costs, and carer burden., Discussion: This trial is the first in the UK to test the effectiveness of Tai Chi to improve balance among PWD. The trial will inform a future study that will be the first in the world to use Tai Chi in a trial to prevent falls among PWD., Trial Registration: NCT02864056 .

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.

Objective: To test the feasibility of running a randomised controlled trial of a preconsultation web-based intervention (Presenting Asking Checking Expressing (PACE-D)) to improve the quality of care and clinical outcomes in patients with diabetes., Design and Setting: A feasibility study (with randomisation) conducted at outpatient diabetes clinics at two secondary care hospitals in Devon, UK., Participants: People with diabetes (type 1 and type 2) attending secondary care general diabetes outpatient clinics., Intervention: The PACE-D, a web-based tool adapted for patients with diabetes to use before their consultation to generate an agenda of topics to discuss with their diabetologist., Outcomes: The percentage of eligible patients who were recruited and the percentage of participants for whom routine glycosylated haemoglobin (HbA1c) data (the putative primary outcome) could be extracted from medical notes and who completed secondary outcome assessments via questionnaire at follow-up were reported., Results: In contrast with the planned recruitment of 120 participants, only 71 participants were randomised during the 7-month recruitment period. This comprised 18.7% (95% CI 14.9% to 23.0%) of those who were eligible. Mean (SD) age of the participants was 56.5 (12.4) years and 66.2% had type 1 diabetes. Thirty-eight patients were randomised to the intervention arm and 33 to the control arm. HbA1c data were available for only 73% (95% CI 61% to 83%) of participants at the 6 months follow-up. The questionnaire-based data were collected for 66% (95% CI 54% to 77%) of the participants at 6 months follow-up. Participants reported that the PACE-D tool was easy to use., Conclusions: A randomised controlled trial of the preconsultation web-based intervention as set out in our current protocol is not feasible without significant modification to improve recruitment and follow-up of participants. The study also provides insights into the feasibility and challenges of conducting complex intervention trials in everyday clinical practice., Trial Registration: ISRCTN75070242., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner., Methods: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival., Findings: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084)., Interpretation: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection., Funding: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

This is an analysis in 171 patients comparing BEAM-Auto and BEAM-Allo (alemtuzumab)-hematopoietic stem cell transplantation in relapsed follicular lymphoma. BEAM-Allo group had a lower 10 years cumulative incidence of relapse(31.4% vs 55.1%, p=0.042), a trend to a plateau in survival but no statistical differences in OS or DFS, and a TRM of 24%. When transplanted in CR BEAM-Allo patients had better OS and DFS. Incidence of acute and chronic GVHD was 16.6% and 22%. 29% of BEAM-Allo patients received DLI (all but two remain in CR and alive). Our data supports Allo-HSCT as a potential curative treatment for selected patients with FL., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Background and Objectives: Determining responsiveness of measures across different samples and settings is important for selecting measures of mobility and understanding multiple sclerosis (MS) study results. Currently such information is limited., Methods: This exploratory study examined the relative responsiveness of four mobility measures (walking velocity, 6-minute walk distance, Rivermead Mobility Index and MS Walking Scale) in a community sample (n = 70), after three annual assessments. Distribution based estimates and anchor-based methods (comparison against transition questions) determined responsiveness. A head-to-head comparison was made., Results: While variations in individuals occurred, the group mean change scores for all measures was small, suggesting that there was minimal deterioration in the total sample. Consistent with this, total sample Effect Size (ES) was negligible to small (ES -0.32 to +0.03) for all measures. Differentiation between sub-groups, defined by the participants' perception of change in mobility over the past year (transition questions), showed that some instruments could detect clinically significant changes (small sample sizes limited this interpretation). Correlation analyses between change scores demonstrated that these measures captured related, but different information (r < 0.364)., Conclusions: The measures were broadly comparable in detecting mobility changes in this community sample. These correlations highlight that in selection of measures, one should also consider the discrete mobility dimension that the intervention intends to impact.

Introduction: Diabetes is a chronic condition associated with many long-term complications. People with diabetes need to actively manage their condition, which can be complex. In consultations with healthcare professionals, patients receive advice about their diabetes but do not always discuss things which concern them, perhaps because of the perceived limited time or embarrassment. We want to test a 'preconsultation' intervention in which the patient is supported by a healthcare assistant to complete a web-based intervention aimed at producing an agenda to help them identify important areas for discussion in the consultation. Use of this agenda may enable the patient to play a more active role in that consultation and consequently become more confident, and hence more successful, in managing their condition., Methods and Analysis: In this pilot randomised controlled trial, 120 people with diabetes will be randomised with equal allocation to receive the intervention or usual clinical care. The primary outcome is reduction in glycosylated haemoglobin(HbA1c). Secondary outcomes are patient-reported communication, enablement, self-care activity, diabetes-dependent quality of life, empowerment, satisfaction, health-related quality of life and resource use. The aim of the pilot study was to estimate parameters to inform the design of the definitive trial. Follow-up on quantitative outcomes will be at 3 and 6 months. A nested qualitative study will collect data on the patients' experiences of producing an agenda. Resource use data and medication use will also be collected via a review of medical records for a sample of participants., Ethics and Dissemination: Approval was granted by the NHS Research Ethics Committee North West-Preston (13/NW/0123). Dissemination will include publication of quantitative and qualitative findings, and experience of public involvement in peer-reviewed journals. Results will also be disseminated to trial participants via workshops led by lay coapplicants., Trial Registration: ISRCTN75070242.

Despite being of the myeloid lineage, acute myeloid leukaemia (AML) blasts are of low immunogenicity, probably because they lack the costimulatory molecule CD80 and secrete immunosuppressive factors. We have previously shown that in vitro stimulation of autologous peripheral blood mononuclear cells (PBMCs) with primary AML cells modified to express CD80 and IL-2 promotes proliferation, secretion of Th1 cytokines and expansion of activated CD8(+) T cells. In this study, we show that allogeneic effector cells (from a healthy donor or AML patients) when stimulated with IL-2/CD80 modified AML blasts were able to induce the lysis of unmodified AML blasts. Effector cells stimulated with IL-2/CD80AML blasts had higher lytic activity than cells stimulated with AML cells expressing CD80 or IL-2 alone. Similarly, AML patient PBMCs primed with autologous IL-2/CD80 AML cells had a higher frequency of IFN-gamma secreting cells and show cytotoxicity against autologous, unmodified blasts. Crucially, the response appears to be leukaemia specific, since stimulated patient PBMCs show higher frequencies of IFN-gamma secreting effector cells in response to AML blasts than to remission bone marrow cells from the same patients. Although studied in a small number of heterogeneous patient samples, the data are encouraging and support the continuing development of vaccination for poor prognosis AML patients with autologous cells genetically modified to express IL-2/CD80.

Immunotherapeutic strategies are increasingly being explored as a method of enhancing anti-tumour immune responses in patients with acute myeloid leukaemia (AML). Regulatory CD4(+) T cells (Tregs) suppress effector T and natural killer (NK) cells and therefore pose a potential challenge to the efficacy of immunotherapy. AML cells transduced with a lentivirus expressing CD80 (B7.1) and IL2 (LV-CD80/IL2) are capable of stimulating T and NK cell cytotoxicity in vitro. This study examines the effect of CD80/IL2 modified AML cells on Treg number and function. We report a significant increase in the number of CD8(+) T cells (P = 0.046) CD3(-)CD56(+) NK cells (P = 0.028) and CD3(+)CD4(+)CD25(high)Foxp3(+) Tregs (P = 0.043) following stimulation for 7 days with allogeneic LV-CD80/IL2 AMLs. In contrast, autologous LV-CD80/IL2 AML cell cultures provide a weaker stimulation with a lower number of CD8(+) T cells (P = 0.011) and no change in NK cell or Treg numbers. However, an increase in cytotoxic CD8(+) T cells and NK cells are detected following both allogeneic and autologous LV-CD80/IL2 stimulation as demonstrated by an increase in IFN-gamma and CD107a expression. Despite the presence of increased numbers of Tregs with suppressive activity in a subset of cultures, increased lysis of unmodified AMLs was still achieved following allogeneic (day 0, 2.2%; day 7, 20.4%) and more importantly, autologous LV-CD80/IL2 culture in which AML patients had recently received intensive chemotherapy (day 0, 0%; day 7, 16%). Vaccination with LV-CD80/IL2 therefore provides a potential strategy to enhance anti-leukaemia immune responses without a concomitant stimulation of Treg-mediated inhibition of cytotoxic immunological responses.

Immunological responses are increasingly recognised as being important in the initiation and progression of myelodysplastic syndrome (MDS). Indeed, autoimmune diseases commonly occur in association with MDS, particularly in subtypes with a low risk of leukaemic transformation. This study showed for the first time that the numbers of CD3(+) CD4(+) IL-17 producing T cells (Th17) were markedly increased in low risk MDS compared with high risk MDS (P < 0.01). An inverse relationship between the numbers of Th17 cells and naturally occurring CD4(+)CD25(high) FoxP3(+) regulatory T cells (Tregs) were also described. The Th17:Tregs ratio was significantly higher in low risk disease (P < 0.005) compared with high risk MDS and was correlated with increased bone marrow (BM) apoptosis (P < 0.01). Tregs from MDS patients suppressed interferon-gamma (IFN-gamma) secretion by effector CD4(+) T cells but had no effect on interleukin (IL)-17 production. In addition, the serum levels of IL-7, IL-12, RANTES and IFN-gamma are significantly elevated in low risk MDS, while inhibitory factors, such as IL-10 and soluble IL-2 receptor, are significantly higher in high risk disease. The 'unfavourable' Th17:Tregs ratio in low risk MDS may explain the higher risk of autoimmunity and the improved response to immune suppression in patients with low risk MDS compared to those with high risk disease.

Bacteriophage Cro proteins bind to target DNA as dimers but do not all dimerize with equal strength, and differ in fold in the region of the dimer interface. We report the structure of the Cro protein from Enterobacteria phage N15 at 1.05 A resolution. The subunit fold contains five alpha-helices and is closely similar to the structure of P22 Cro (1.3 A backbone room mean square difference over 52 residues), but quite different from that of lambda Cro, a structurally diverged member of this family with a mixed alpha-helix/beta-sheet fold. N15 Cro crystallizes as a biological dimer with an extensive interface (1303 A(2) change in accessible surface area per dimer) and also dimerizes in solution with a K(d) of 5.1 +/- 1.5 microM. Its dimerization is much stronger than that of its structural homolog P22 Cro, which does not self-associate detectably in solution. Instead, the level of self-association and interfacial area for N15 Cro is similar to that of lambda Cro, even though these two orthologs do not share the same fold and have dimer interfaces that are qualitatively different in structure. The common Cro ancestor is thought to be an all-helical monomer similar to P22 Cro. We propose that two Cro descendants independently developed stronger dimerization by entirely different mechanisms.

Proteins that share common ancestry may differ in structure and function because of divergent evolution of their amino acid sequences. For a typical diverse protein superfamily, the properties of a few scattered members are known from experiment. A satisfying picture of functional and structural evolution in relation to sequence changes, however, may require characterization of a larger, well chosen subset. Here, we employ a "stepping-stone" method, based on transitive homology, to target sequences intermediate between two related proteins with known divergent properties. We apply the approach to the question of how new protein folds can evolve from preexisting folds and, in particular, to an evolutionary change in secondary structure and oligomeric state in the Cro family of bacteriophage transcription factors, initially identified by sequence-structure comparison of distant homologs from phages P22 and lambda. We report crystal structures of two Cro proteins, Xfaso 1 and Pfl 6, with sequences intermediate between those of P22 and lambda. The domains show 40% sequence identity but differ by switching of alpha-helix to beta-sheet in a C-terminal region spanning approximately 25 residues. Sedimentation analysis also suggests a correlation between helix-to-sheet conversion and strengthened dimerization.

Haematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). Developing conditioning regimens with low toxicity, at the same time as preserving an effective graft versus tumour response, is pivotal to expanding the scope for allogeneic transplantation in older patients with MDS. With the introduction of reduced intensity conditioned regimens, transplant centres worldwide are able to offer allogeneic HSCT to a much larger cohort of patients. Graft versus host disease (GvHD) remains a significant cause of morbidity and mortality, however with the use of T-cell depletion, centres have been able to utilise volunteer unrelated donors with an increasing degree of HLA disparity. The graft versus dysplasia effect resulting from allogeneic HSCT and the infusion of donor leukocytes has led to a greater understanding of the immunological mechanisms that govern outcome following transplantation in MDS.