Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. FUNDING: UK National Institute for Health and Care Research.

Cues for word-learning during shared book-reading and guided play in preschool.

The present study examines the perceptual, linguistic, and social cues that were associated with preschoolers' (4;11) growth in word-learning during shared book-reading and guided play activities. Small groups of three preschoolers (n = 30) and one adult were video-recorded during an intervention study in which new vocabulary words were explicitly taught. Adult use of taught words was coded for perceptual and linguistic cues and type of social interaction. Hearing taught words used in the book text and learning information about words' meanings during play was positively associated with growth in word-learning. Adult use of words in responsive, or child-initiated, interactions was positively associated with word-learning growth in both book-reading and play, while adult-initiated use of words was negatively associated with word-learning growth in both settings.

Platform adaptive trial of novel antivirals for early treatment of COVID-19 In the community (PANORAMIC): protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease.

INTRODUCTION: There is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. METHODS AND ANALYSIS: PANORAMIC is a UK-wide, open-label, prospective, adaptive, multiarm platform, randomised clinical trial that evaluates antiviral treatments for COVID-19 in the community. A master protocol governs the addition of new antiviral treatments as they become available, and the introduction and cessation of existing interventions via interim analyses. The first two interventions to be evaluated are molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid). ELIGIBILITY CRITERIA: community-dwelling within 5 days of onset of symptomatic COVID-19 (confirmed by PCR or lateral flow test), and either (1) aged 50 years and over, or (2) aged 18-49 years with qualifying comorbidities. Registration occurs via the trial website and by telephone. Recruitment occurs remotely through the central trial team, or in person through clinical sites. Participants are randomised to receive either usual care or a trial drug plus usual care. Outcomes are collected via a participant-completed daily electronic symptom diary for 28 days post randomisation. Participants and/or their Trial Partner are contacted by the research team after days 7, 14 and 28 if the diary is not completed, or if the participant is unable to access the diary. The primary efficacy endpoint is all-cause, non-elective hospitalisation and/or death within 28 days of randomisation. Multiple prespecified interim analyses allow interventions to be stopped for futility or superiority based on prespecified decision criteria. A prospective economic evaluation is embedded within the trial. ETHICS AND DISSEMINATION: Ethical approval granted by South Central-Berkshire REC number: 21/SC/0393; IRAS project ID: 1004274. Results will be presented to policymakers and at conferences, and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN30448031; EudraCT number: 2021-005748-31.

Intranasal air sampling in homes: relationships among reservoir allergen concentrations and asthma severity.

BACKGROUND: The relationship among inhaled allergen exposure, sensitization, and asthma severity is unknown. OBJECTIVES: To investigate the relationship among personal allergen exposure, reservoir dust allergen concentrations, and physiological measures of asthma severity; to examine the numbers of particles inspired that react with autologous IgE and IgG4. METHODS: A total of 117 patients with asthma wore 5 nasal air samplers (NASs) at home: 1 each for exposure to mite, cat and dog allergens, NAS-IgE, and NAS-IgG4. NASs were processed by HALOgen assay for allergen measurement and incubated with autologous serum for detection of NAS-IgE and NAS-IgG4. Reservoir allergen concentrations were measured by ELISA. Subjects' asthma severity was ascertained by measurement of lung function, exhaled nitric oxide, and nonspecific bronchial reactivity to histamine. RESULTS: Nasal air sampler counts correlated with reservoir concentrations for cat (r=0.31; P=.001) and dog (r=0.20; P=.03) but not mite allergen (r=0.001; P=1.0). There was no significant relationship between sensitization with exposure measured by NAS to any allergen and PD20FEV1 (F[3,60]=1.60; P=.20); however, sensitization with exposure in dust reservoirs had significant effects on PD20FEV1 for any allergen (F[3,59]=3.12; P=.03), cat (F[3,59]=3.77; P=.01), and mite (F[3,59]=2.78; P=.05), but not dog (F[3,59]=1.06; P=.37). We repeated the analysis with separate variables for sensitization and exposure, controlling for the confounders; sensitization but not exposure conferred lower PD20FEV1 values. However, increasing cat allergen exposure was associated with improving bronchial reactivity in not cat-sensitized patients. NAS-IgE and NAS-IgG4 counts bore no relationship to any measure of asthma severity. CONCLUSION: Nasal air samplers confer no advantage over reservoir dust analysis for studies of asthma severity. CLINICAL IMPLICATIONS: In common with other measures of exposure, single nasal air samples do not provide a useful measure of home allergen exposure for the individual patient with allergic asthma.