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A two-step process, in which circulating levels of amyloid P are reduced and then anti–serum amyloid P antibody is given to activate macrophage clearance mechanisms of tissue deposits, appears to reduce amyloid deposits in liver and some other organs. In systemic amyloidosis, the extracellular deposition of normally soluble plasma proteins as insoluble amyloid fibrils damages the structure and function of tissues and organs. 1 Current treatment consists of support or replacement of failing organs and measures to reduce the abundance of the amyloid fibril precursor protein. 1 , 2 A sufficient reduction of precursor supply arrests the accumulation of amyloid and can reduce morbidity and mortality. However, amyloid regression is very slow and often does not occur at all, in contrast to the usually swift clearance of other extracellular debris and efficient tissue remodeling — for example, after trauma. At least 65% . . .

Background Explainer animations are a means to communicate aspects of clinical trials to participants in a more engaging and accessible way. Delivered well these have the potential to enhance recruitment and retention. The range of media technology used to deliver this material is expanding rapidly but is highly fragmented. Usage of explainer animations across the UK is unknown, the aim of this research was to determine current usage across the 52 registered UK Clinical Research Collaboration (UKCRC) Clinical Trials Units (CTUs) to understand the current landscape and any barriers that could be preventing wider uptake of this functionality. Methods A survey link was emailed to all UKCRC CTU Directors and Trial Management Leads to ascertain current usage of explainer animations within their CTU. The survey ran between 01 February 2023 and 07 March 2023. Results Responses were received from 35 CTUs—representing a response rate of 67%. 24 CTUs (69%) reported that they had created/used at least one explainer animation within their unit, although the usage, cost, length and production activities varied among the units. Conclusions The survey showed that a high proportion of the UKCRC CTUs have used explainer animations to provide information to participants about clinical studies. For those not using the technology yet, the most common reasons cited were a lack of expertise, lack of resources and costs to produce them. One of the desired outcomes of this project is the creation of a free-to-use library of animations to encourage wider uptake and avoid duplication.

Background Animated short videos used to explain a concept or project are often called animated explainer videos (AEVs). AEVs can supplement or provide an alternative to participant information sheets as a means of giving information about clinical research to potential participants. Current use of AEVs tends to focus on the specifics of a particular trial, yet there are many common aspects of clinical research regardless of the interventions being investigated that can be poorly covered in current trial materials. The EXPLAIN initiative aimed to determine the top generic clinical trial topics considered most important by different UK trial stakeholders. The top three topics were then turned into AEVs and have been made freely available for use. Method A list of generic clinical trial topics which often need explaining to potential trial participants when they are approached to take part in research was developed. Using a two-round Delphi survey of stakeholder groups (trial participants, patients, members of the public, site staff and clinical trials unit staff), the list of topics was expanded and prioritised to identify the topics most in need of clear explanation. The top three topics formed the basis of three AEVs, co-developed with patient and public partners. Results Two hundred twenty-eight responses were received to the first round of the Delphi survey, and 167 of these respondents also completed the second round of the survey. The three topics prioritised for creation of animated explainer videos were as follows: (1) What is consent? (2) Who decides what treatment I get/What is randomisation? (3) Is it safe to take part in a trial/How do you know a trial is safe? Following virtual meetings with patient and public partners recruited from the Delphi respondents, a script for each AEV was co-produced before being developed into an AEV by a company specialising in animated video production. Conclusion There are a wide range of generic concepts in which the use of animated explainer videos could be useful to improve participant understanding of clinical research. Via consensus survey across multiple stakeholders, we have determined a hierarchy of the importance of explaining these concepts. We envisage that the three AEVs created from this project will form the basis of a readily accessible library of animations to be utilised by trialists.

Background The promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients. Methods A prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients [median age 55 (19–84), 73 % male, APACHE II score 18 (5–37) with a gastric residual volume ≥200 mL]. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg ( n  = 15) camicinal and placebo ( n  = 8) using the 13 C-octanoic acid breath test (BTt 1/2 ), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively. Results Following 50 mg enteral camicinal, there was a trend to accelerated gastric emptying [adjusted geometric means: pre-treatment BTt 1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC 240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72)]. When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt 1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC 240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment. Conclusions When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients. Trial registration The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ).

The A118G single-nucleotide polymorphism (SNP rs1799971) in the μ-opioid receptor gene, OPRM1, has been much studied in relation to alcohol use disorders. The reported effects of allelic variation at this SNP on alcohol-related behaviors, and on opioid receptor antagonist treatments, have been inconsistent. We investigated the pharmacogenetic interaction between A118G variation and the effects of two μ-opioid receptor antagonists in a clinical lab setting. Fifty-six overweight and moderate-heavy drinkers were prospectively stratified by genotype (29 AA homozygotes, 27 carriers of at least 1 G allele) in a double-blind placebo-controlled, three-period crossover design with naltrexone (NTX; 25 mg OD for 2 days, then 50 mg OD for 3 days) and GSK1521498 (10 mg OD for 5 days). The primary end point was regional brain activation by the contrast between alcohol and neutral tastes measured using functional magnetic resonance imaging (fMRI). Secondary end points included other fMRI contrasts, subjective responses to intravenous alcohol challenge, and food intake. GSK1521498 (but not NTX) significantly attenuated fMRI activation by appetitive tastes in the midbrain and amygdala. GSK1521498 (and NTX to a lesser extent) significantly affected self-reported responses to alcohol infusion. Both drugs reduced food intake. Across all end points, there was less robust evidence for significant effects of OPRM1 allelic variation, or for pharmacogenetic interactions between genotype and drug treatment. These results do not support strong modulatory effects of OPRM1 genetic variation on opioid receptor antagonist attenuation of alcohol- and food-related behaviors. However, they do support further investigation of GSK1521498 as a potential therapeutic for alcohol use and eating disorders.

Rationale Translational research implicates the mu opioid neurochemical system in hedonic processing, but its role in dissociable high-level cognitive functions is not well understood. Binge-eating represents a useful model of ‘behavioural addiction’ for exploring this issue. Objective The aim of this study was to objectively assess the cognitive effects of a mu opioid receptor antagonist in obese individuals with binge-eating symptoms. Methods Adults with moderate to severe binge-eating and body mass index ≥30 kg/m 2 received 4 weeks of treatment with a mu opioid receptor antagonist (GSK1521498) 2 or 5 mg per day, or placebo, in a double-blind randomised parallel design. Neuropsychological assessment was undertaken at baseline and endpoint to quantify processing bias for food stimuli (visual dot probe with 500- and 2,000-ms stimulus presentations and food Stroop tasks) and other distinct cognitive functions (N-back working memory, sustained attention, and power of attention tasks). Results GSK1521498 5 mg/day significantly reduced attentional bias for food cues on the visual dot probe task versus placebo ( p  = 0.042), with no effects detected on other cognitive tasks (all p  > 0.10). The effect on attentional bias was limited to the longer stimulus duration condition in the higher dose cohort alone. Conclusions These findings support a central role for mu opioid receptors in aspects of attentional processing of food cues but militate against the notion of major modulatory influences of mu opioid receptors in working memory and sustained attention. The findings have implications for novel therapeutic directions and suggest that the role of different opioid receptors in cognition merits further research.

The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. UK National Institute for Health and Care Research

Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031 In this clinical trial, the authors show that a 5-day molnupiravir treatment reduces SARS-CoV-2 viral load in at-risk outpatients by day 5 but mostly fails to clear virus, leads to lower spike antibody response by day 14 and higher virus mutation rates.

No randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation. This study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0–10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation. Between Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference –1·6% [–2·6% to –0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: –1·9% [–2·9% to –0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference –2·1% [–2·9% to –1·5%]; p(sup)>0·99; NNT 47·6; 6 months: –2·5% [–3·3% to –1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference –1·6% [–2·6% to –0·6%]; p(sup)=0·99; 6 months: –1·9% [–2·9% to –0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference –1·4% [–2·3% to –0·4%]; p(sup)>0·99; NNT 71·4; 6 months: –0·5% [–1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up. In a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat. UK Research and Innovation and National Institute for Health and Care Research.

This corrects the article DOI: 10.1038/npp.2016.60