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ObjectiveTo evaluate the contribution of MRI activity and relapses in defining disease activity in Secondary progressive multiple sclerosis (SPMS) patients by analysing real-world data from Adelphi real-world MS Disease Specific Programme (Adelphi-MS-DSP) and to understand whether active SPMS (aSPMS) and non-active SPMC (naSPMS) are mutually exclusive groups in EXPAND.MethodsAdelphi-MS-DSP was a non-interventional, multinational real-world study (N=37,318). Patients were categorised into aSPMS (⩾1 new lesion on the most recent MRI and/or ⩾1 relapse in the last 12-months) and naSPMS groups. In EXPAND, disease activity was defined as relapses in the 2-years before screening and with/without ⩾1 gadolinium-enhancing (Gd+) T1 lesion at baseline. Demographics, MRI and relapse status were analysed descriptively.ResultsSPMS from the Adelphi-MS-DSP were categorised as aSPMS (n=1889) and naSPMS (n=665). Disease activity for aSPMS was based on MRI lesions (59.1%), relapses (12.6%), and both (28.3%). In EXPAND, 52.6% of patients (n/N=866/1645) who had no relapse in the 2-years prior to screening and no Gd+ T1 lesions at baseline were categorised under naSPMS; of these who were on placebo, 52.7% experienced on-study relapse and/or MRI activity.ConclusionsIn both real-world and clinical studies, MRI activity appears to be a more sensitive measure of disease activity versus relapses. Funding: Novartis Pharma AG, Basel, Switzerland.

Biofilm infections are a global public health threat, necessitating new treatment strategies. Biofilm formation also contributes to the development and spread of multidrug-resistant (MDR) bacterial strains. Biofilm-associated chronic infections typically involve colonization by more than one bacterial species. The co-existence of multiple species of bacteria in biofilms exacerbates therapeutic challenges and can render traditional antibiotics ineffective. Polymeric nanoparticles offer alternative antimicrobial approaches to antibiotics, owing to their tunable physico-chemical properties. Here, we report the efficacy of poly(oxanorborneneimide) (PONI)-based antimicrobial polymeric nanoparticles (PNPs) against multi-species bacterial biofilms. PNPs showed good dual-species biofilm penetration profiles as confirmed by confocal laser scanning microscopy. Broad-spectrum antimicrobial activity was observed, with reduction in both bacterial viability and overall biofilm mass. Further, PNPs displayed minimal fibroblast toxicity and high antimicrobial activity in an in vitro co-culture model comprising fibroblast cells and dual-species biofilms of Escherichia coli and Pseudomonas aeruginosa. This study highlights a potential clinical application of the presented polymeric platform.

To date there are no evidence-based comprehensive interventions for use in school settings. There are numerous barriers to delivery of high-quality interventions in schools that have limited the transfer of research-based interventions to school settings. Modular Approach to Autism Programing for Schools (MAAPS) is a framework for implementation of evidence-based interventions in school settings that is designed to address these barriers. The development and initial evaluation of MAAPS was conducted using an implementation-science framework and results indicate that MAAPS is aligned with needs and resources available in schools, that it had excellent social validity, and that there is good evidence that MAAPS is effective for addressing core and associated features of autism in educational settings.

Concomitant administration of COVID-19 and influenza vaccines could reduce burden on health-care systems. We aimed to assess the safety of concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine. In this multicentre, randomised, controlled, phase 4 trial, adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomly assigned (1:1) to receive concomitant administration of either an age-appropriate influenza vaccine or placebo alongside their second dose of COVID-19 vaccine. 3 weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed up for 6 weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reactions in the 7 days after first trial vaccination(s), with a difference of less than 25% considered non-inferior. Analyses were done on an intention-to-treat basis. Local and unsolicited systemic reactions and humoral responses were also assessed. The trial is registered with ISRCTN, ISRCTN14391248. Between April 1 and June 26, 2021, 679 participants were recruited to one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent influenza vaccine. 340 participants were assigned to concomitant administration of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo at day 21, and 339 participants were randomly assigned to concomitant administration of placebo and a second dose of COVID-19 vaccine at day 0 followed by influenza vaccine at day 21. Non-inferiority was indicated in four cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk difference for influenza vaccine minus placebos −1·29%, 95% CI −14·7 to 12·1), BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, −6·27 to 18·6), BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (–12·9%, −34·2 to 8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, −13·3 to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the 0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine 10·3%, −5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza vaccine 6·75%, −11·8 to 25·3). Most systemic reactions to vaccination were mild or moderate. Rates of local and unsolicited systemic reactions were similar between the randomly assigned groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected. Concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raises no safety concerns and preserves antibody responses to both vaccines. Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunisation season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need. National Institute for Health Research Policy Research Programme

Implementation of evidence-based practices for autistic students must be informed by robust research literature. Randomized-controlled trials (RCTs) are often considered a “gold standard” methodology for determining the effectiveness of interventions. However, the complex nature of schools presents challenges for implementing successful RCTs. We review common challenges that researchers may face when implementing RCTs of interventions for autistic students in school settings. Additionally, we provide recommendations to researchers for avoiding and addressing such challenges, based on our own experience conducting a school-based RCT. Limitations and directions for future research are also discussed.

As the prevalence of autistic children receiving special education continues to increase, educators are expected to identify and implement evidence-based interventions for autistic students. Unfortunately, there are numerous barriers to implementation of evidence-based interventions in schools and educators report a lack of adequate training regarding the needs of autistic students and appropriate intervention approaches. Modular approaches to intervention are a promising but untested strategy for helping educators receive training on evidence-based interventions and support with implementation. This study uses mixed methods to explore the initial feasibility of the Modular Approach to Autism Programs in Schools (MAAPS) in typical school settings. Key indicators of feasibility are presented using the RE-AIM framework (Glasgow et al. American journal of public health , 89 (9), 1322-1327, Glasgow et al., 1999 ), with emphasis on intervention fidelity, social validity, and promise of efficacy. Additionally, directions for future research are discussed.

Background Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD). Methods/design The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child–Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival. Discussion The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care. Ethics and dissemination The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation. Trial registration EUDRACT reference number: 2018–002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

Nat. Genet. 42, 579–589 (2010); published online 27 June 2010; corrected after print 27 August 2010 In the version of this article initially published, there was an error in Table 1. Specifically, for rs5945326, the risk and non-risk alleles were reversed. The correct risk allele at rs5945326 is A, the non-risk allele is G and the risk allele frequency in HapMap CEU is 0.