Search

In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.

Background: Delivering hospital-level care with comprehensive geriatric assessment (CGA) in the home is one approach to deal with the increased demand for bed-based hospital care, but clinical effectiveness is uncertain. Objective: To assess the clinical effectiveness of admission avoidance hospital at home (HAH) with CGA for older persons. Design: Multisite randomized trial. (ISRCTN registry number: ISRCTN60477865) Setting: 9 hospital and community sites in the United Kingdom. Patients: 1055 older persons who were medically unwell, were physiologically stable, and were referred for a hospital admission. Intervention: Admission avoidance HAH with CGA versus hospital admission with CGA when available using 2:1 randomization. Measurements: The primary outcome of living at home was measured at 6 months. Secondary outcomes were new admission to long-term residential care, death, health status, delirium, and patient satisfaction. Results: Participants had a mean age of 83.3 years (SD, 7.0). At 6-month follow-up, 528 of 672 (78.6%) participants in the CGA HAH group versus 247 of 328 (75.3%) participants in the hospital group were living at home (relative risk [RR], 1.05 [95% CI, 0.95 to 1.15]; P = 0.36); 114 of 673 (16.9%) versus 58 of 328 (17.7%) had died (RR, 0.98 [CI, 0.65 to 1.47]; P = 0.92); and 37 of 646 (5.7%) versus 27 of 311 (8.7%) were in long-term residential care (RR, 0.58 [CI, 0.45 to 0.76]; P < 0.001). Limitation: The findings are most applicable to older persons referred from a hospital short-stay acute medical assessment unit; episodes of delirium may have been undetected. Conclusion: Admission avoidance HAH with CGA led to similar outcomes as hospital admission in the proportion of older persons living at home as well as a decrease in admissions to long-term residential care at 6 months. This type of service can provide an alternative to hospitalization for selected older persons. Primary Funding Source: The National Institute for Health Research Health Services and Delivery Research Programme (12/209/66).

Correction to: Digital messaging to support control for type 2 diabetes (StAR2D): a multicentre randomised controlled trial, available at: https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-021-11874-7.

ObjectivesColchicine has been proposed as a COVID-19 treatment, but its effect on time to recovery is unknown. We aimed to determine whether colchicine is effective at reducing time to recovery and COVID-19 related hospitalisations/deaths among people in the community.DesignProspective, multicentre, open-label, multi-arm, adaptive Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE).SettingNational trial run remotely from a central trial site and at multiple primary care centres across the United Kingdom.ParticipantsAdults aged ≥65, or ≥18 years with comorbidities or shortness of breath, and unwell ≤14 days with suspected COVID-19 in the community.InterventionsParticipants were randomised to usual care, usual care plus colchicine (500µg daily for 14 days), or usual care plus other interventions.Main outcome measuresThe co-primary endpoints were time to first self-reported recovery, and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. The hypothesis for the time to recovery endpoint is evaluated first, and if superiority is declared on time to recovery, the hypothesis for the second co-primary endpoint of hospitalisation/death is then evaluated. To determine futility, we pre-specified a clinically meaningful benefit in time to first reported recovery as a hazard ratio of 1.2 or larger (equating to approximately 1.5 days benefit in the colchicine arm, assuming 9 days recovery in the usual care arm).ResultsThe trial opened on April 2, 2020, with randomisation to colchicine starting on March 04, 2021 and stopping on May 26, 2021, because the pre-specified time to recovery futility criterion was met. The primary analysis model included 2755 SARS-CoV-2 positive participants, randomised to colchicine (n=156), usual care (n=1145), and other treatments (n=1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.919 [95% credible interval 0.72 to 1.16] and an estimated increase of 1.14 days [−1.86 to 5.21] in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. Results were similar in comparisons with concurrent controls. COVID-19 related hospitalisations/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 [0.28 to 1.89] and an estimated difference of −0.4% [−2.7% to 2.4]. One serious adverse event occurred in the colchicine group and one in usual care.ConclusionsColchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community.Trial registrationISRCTN86534580.

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Azithromycin, an antibiotic with potential antiviral and anti-inflammatory properties, has been used to treat COVID-19, but evidence from community randomised trials is lacking. We aimed to assess the effectiveness of azithromycin to treat suspected COVID-19 among people in the community who had an increased risk of complications. Methods: In this UK-based, primary care, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE), we randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. The trial had two coprimary endpoints measured within 28 days from randomisation: time to first self-reported recovery, analysed using a Bayesian piecewise exponential, and hospital admission or death related to COVID-19, analysed using a Bayesian logistic regression model. Eligible participants with outcome data were included in the primary analysis, and those who received the allocated treatment were included in the safety analysis. The trial is registered with ISRCTN, ISRCTN86534580. Findings: The first participant was recruited to PRINCIPLE on April 2, 2020. The azithromycin group enrolled participants between May 22 and Nov 30, 2020, by which time 2265 participants had been randomly assigned, 540 to azithromycin plus usual care, 875 to usual care alone, and 850 to other interventions. 2120 (94%) of 2265 participants provided follow-up data and were included in the Bayesian primary analysis, 500 participants in the azithromycin plus usual care group, 823 in the usual care alone group, and 797 in other intervention groups. 402 (80%) of 500 participants in the azithromycin plus usual care group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days. We found little evidence of a meaningful benefit in the azithromycin plus usual care group in time to first reported recovery versus usual care alone (hazard ratio 1·08, 95% Bayesian credibility interval [BCI] 0·95 to 1·23), equating to an estimated benefit in median time to first recovery of 0·94 days (95% BCI −0·56 to 2·43). The probability that there was a clinically meaningful benefit of at least 1·5 days in time to recovery was 0·23. 16 (3%) of 500 participants in the azithromycin plus usual care group and 28 (3%) of 823 participants in the usual care alone group were hospitalised (absolute benefit in percentage 0·3%, 95% BCI −1·7 to 2·2). There were no deaths in either study group. Safety outcomes were similar in both groups. Two (1%) of 455 participants in the azothromycin plus usual care group and four (1%) of 668 participants in the usual care alone group reported admission to hospital during the trial, not related to COVID-19. Interpretation: Our findings do not justify the routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community. These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antimicrobial resistance, and there is evidence that azithromycin use increased during the pandemic in the UK. Funding: UK Research and Innovation and UK Department of Health and Social Care.

Additional file 2. Baseline process evaluation interview guide.

Additional file 1. Collaborating Centres and supplementary data table.

Additional file 3. Final process evaluation interview guide.

Background Persecutory delusions are a major psychiatric problem and are associated with a wide range of adverse outcomes. Our theoretical model views these delusions as unfounded threat beliefs which persist due to defence behaviours (e.g. avoidance) that prevent disconfirmatory evidence being processed. The treatment implications are that patients need to (1) go into feared situations and (2) not use defence behaviours. This enables relearning of safety and hence paranoia diminution. However, this is very difficult for patients due to their severe anxiety. A solution is to use virtual reality (VR) social situations, which are graded in difficulty and which patients find much easier to enter. We have now automated the provision of cognitive therapy within VR using an avatar coach, so that a therapist is not required and the treatment is scalable. In the THRIVE trial, the automated VR cognitive treatment will be tested against a VR control condition. It will contribute to our wider programme of work developing VR for patients with psychosis. Methods Patients with persistent persecutory delusions in the context of non-affective psychosis will be randomised (1:1) to the automated VR cognitive treatment or VR mental relaxation (control condition). Each VR treatment will comprise approximately four sessions of 30 min. Standard care will remain as usual in both groups. Assessments will be carried out at 0, 2, 4 (post treatment), 8, 16, and 24 weeks by a researcher blind to treatment allocation. The primary outcome is degree of conviction in the persecutory delusion (primary endpoint 4 weeks). Effect sizes will be re-established by an interim analysis of 30 patients. If the interim effect size suggests that the treatment is worth pursuing (d > 0.1), then the trial will go on to test 90 patients in total. Secondary outcomes include real world distress, activity levels, suicidal ideation, and quality of life. Mediation will also be tested. All main analyses will follow the intention-to-treat principle. The trial is funded by the Medical Research Council Developmental Pathway Funding Scheme. Discussion The trial will provide the first test of automated cognitive therapy within VR for patients with psychosis. The treatment is potentially highly scalable for treatment services. Trial registration ISRCTN, ISRCTN12497310. Registered on 14 August 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3198-6) contains supplementary material, which is available to authorized users.

Importance: Deprescribing of antihypertensive medications is recommended for some older patients with polypharmacy and multi-morbidity where the benefits of continued treatment may not outweigh the harms. Objective: This study aimed to establish whether antihypertensive medication reduction is possible without significant changes in systolic blood pressure control or adverse events during a 12-week follow-up period. Design, Setting, and Participants: The OPtimising Treatment for MIld Systolic hypertension in the Elderly (OPTIMISE) study was a randomized, unblinded, non-inferiority trial conducted in 69 primary care sites in England. Participants were aged ≥80 years with systolic blood pressure, This work received joint funding from the National Institute for Health Research (NIHR) Oxford Collaboration for Leadership in Applied Health Research and Care (CLAHRC) at Oxford Health NHS Foundation Trust (ref: P2-501) and the NIHR School for Primary Care Research (SPCR; ref 335).

In this letter, it is reported that the first experimental results are associated with the GAM induced by energetic electrons (eEGAM) in HL-2A Ohmic plasma. The energetic-electrons are generated by parallel electric fields during magnetic reconnection associated with tearing mode (TM). The eEGAM localizes in the core plasma, i.e. in the vicinity of q=2 surface, and is very different from one excited by the drift-wave turbulence in the edge plasma. The analysis indicated that the eEGAM is provided with the magnetic components, whose intensities depend on the poloidal angles, and its mode numbers are jm/nj=2/0. Further, there exist intense nonlinear interactions among eEGAM, BAEs and strong tearing modes (TMs). These new findings shed light on the underlying physics mechanism for the excitation of the low frequency (LF) Alfv\'enic and acoustic uctuations., Comment: 5 pages,4 figures

OBJECTIVES: The Arterial Revascularization Trial (ART) is a randomized comparison of bilateral internal mammary artery (BIMA) versus single internal mammary artery (SIMA) grafting in coronary artery bypass graft (CABG) surgery and is one of the largest randomized trials of surgery ever conducted. ART is also one of the largest studies of contemporary CABG with a high proportion of off-pump surgeries (41%). The objective of this post hoc analysis was to evaluate the surgical process and 1-year outcomes for surgery performed on-pump compared with off-pump. METHODS: ART randomized 3102 patients with multivessel coronary artery disease (CAD) to SIMA or BIMA grafts to determine if BIMA grafts have an additional survival advantage at 10 years. The 1-year interim analysis showed an overall very low mortality and major morbidity rate irrespective of whether the procedure was with an SIMA or BIMA. The surgical process and 1-year outcomes were analysed according to whether surgery was performed on-pump or off-pump. RESULTS: Baseline variables were not statistically significantly different between on- and off-pump surgery within each treatment group after taking account of the effects of clustering by individual surgeons. At both 30 days and 1 year, there was a low incidence of death (1.2%, 2.3%), stroke (1.1%, 1.7%), myocardial infarction (MI) (1.4%, 1.9%), repeat revascularization (0.5%, 1.5%) and wound reconstruction (1.2%). A similar average number of grafts were performed with on- and off-pump surgery (median = 3), but the duration of surgery was 20-30 min and ventilation time ∼2 h shorter with off-pump surgery. Blood loss and platelet transfusions were lower in the off-pump group, with no difference in the need for balloon pump or renal support. Sternal wound reconstruction was similar with off-pump surgery in the SIMA group (0.5 vs 0.6%) and lower with off-pump surgery in the BIMA group (1.4 vs 2.2%). Repeat revascularization was marginally higher in off-pump patients at 30 days (0.8 vs 0.3%) and at 1 year (1.7 vs 1.3%). CONCLUSIONS: The outcomes of contemporary CABG are excellent with low mortality, stroke, myocardial infarction and need for wound reconstruction and repeat revascularization whether performed on-pump or off-pump. CLINICAL TRIAL REGISTRATION: Controlled-trials.com (ISRCTN46552265).

Objective: The aim of this study was to assess long-term effects for women following the use of magnesium sulphate for pre-eclampsia. Design: Assessment at 2-3 years after delivery for women recruited to the Magpie Trial (recruitment in 1998-2001, ISRCTN 86938761), which compared magnesium sulphate with placebo for pre-eclampsia. Setting: Follow up after discharge from hospital at 125 centres in 19 countries across five continents. Population: A total of 7927 women were randomised at the follow-up centres. Of these women, 2544 were not included for logistic reasons and 601 excluded (109 at a centre where

Synapse dysfunction is emerging as a major factor in the pathogenesis of Alzheimer’s disease (AD). Key insights into the pathological mechanisms have been provided through studies of familial AD (FAD) genes. Mutations in the PSEN1 gene account for the vast majority of FAD cases, which are typified by the formation of amyloid plaques, neurofibrillary tangles and neuronal loss. The PSEN1 gene encodes presenilin 1, a polytopic transmembrane protein, which is the catalytic core of a proteolytic enzyme complex known as γ-secretase. γ-secretase mediates the generation of amyloid-β (Aβ) peptides, key constituents of amyloid plaques, and hence it is central to AD pathology. γ-secretase has also been implicated in the proteolysis of a wide range of transmembrane proteins associated with different cellular signalling pathways and functions. However, the precise role that presenilins play in regulating synapse function is not clear. The aim of this thesis is to gain an understanding of the physiological role of presenilin 1 at hippocampal synapses in anticipation that this may provide a greater understanding of the mechanisms that underlie synaptic dysfunction during AD. This study provides evidence that presenilin is implicated in modulating spontaneous excitatory synaptic transmission in hippocampal neurons in dissociated and slice cultures. Further experiments have revealed a role for presenilin in modulating synapse number but not neurotransmitter release probability, and calcium imaging suggests that γ-secretase activity is dispensable for regulation of cellular calcium homeostasis. In addition, experiments using pharmacological inhibitors of Aβ precursor protein processing and Aβ peptide generation have uncovered synaptic roles for γ-secretase that are potentially distinct from those of β-secretase. Together these findings suggest a role for presenilin in regulating basal glutamatergic synaptic transmission and synapse structure of hippocampal neurons.

Objective To assess the long-term effects of in utero exposure to magnesium sulphate for children whose mothers had pre-eclampsia. Design Assessment at 18 months of age for children whose mothers were recruited to the Magpie Trial (recruitment 1998–2001 ISRCTN 86938761), which compared magnesium sulphate with placebo. Setting Follow-up of children born at 125 centres in 19 countries across five continents. Population A total of 6922 children were born to women randomised before delivery at follow-up centres. Of these, 2271 were not included for logistic reasons and 168 were excluded (101 at a centre where

We have studied the vibrational properties of thin C60 overlayers deposited on ideally H-terminated Si(111) surfaces, by multiple infrared reflection and high-resolution electron energy-loss spectroscopies. We find that the Si-H interface remains intact upon C60 deposition: the Si-H stretching mode frequency, initially at 2083.8 cm-1, shifts downward to 2062 cm-1, and broadens while keeping the same integrated intensity. Due to the symmetry-breaking effect at the surface on the adsorbed C60 molecules, a new IR band is observed at 1445 cm-1 which is mainly s-polarised. No evidence for chemical interaction between C60 and H/Si(111)-(1 x 1) is found, pointing to van der Waals-type bonding. From the relative intensities of the dipole-active and -inactive modes in HREELS in the specular direction, and from the angular width of the scattered elastic peak, the growth of an ordered film is inferred.

Physical review / B 50(16), 11981 - 11995 (1994). doi:10.1103/PhysRevB.50.11981, Published by Inst., Woodbury, NY

Background Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. Methods We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2–4 consecutive days no later than 7 days from baseline. It will continue 4–5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2–3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. Discussion The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. Trial registration ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3336-1) contains supplementary material, which is available to authorized users.

The precise contribution of the cadherin-beta-catenin synapse adhesion complex in the functional and structural changes associated with the pre- and postsynaptic terminals remains unclear. Here we report a requirement for endogenous beta-catenin in regulating synaptic strength and dendritic spine morphology in cultured hippocampal pyramidal neurons. Ablating beta-catenin after the initiation of synaptogenesis in the postsynaptic neuron reduces the amplitude of spontaneous excitatory synaptic responses without a concurrent change in their frequency and synapse density. The normal glutamatergic synaptic response is maintained by postsynaptic beta-catenin in a cadherin-dependent manner and requires the C-terminal PDZ-binding motif of beta-catenin but not the link to the actin cytoskeleton. In addition, ablating beta-catenin in postsynaptic neurons accompanies a block of bidirectional quantal scaling of glutamatergic responses induced by chronic activity manipulation. In older cultures at a time when neurons have abundant dendritic spines, neurons ablated for beta-catenin show thin, elongated spines and reduced proportion of mushroom spines without a change in spine density. Collectively, these findings suggest that the cadherin-beta-catenin complex is an integral component of synaptic strength regulation and plays a basic role in coupling synapse function and spine morphology.