Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC): a randomised controlled trial

Background: 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. Methods: 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. Findings: 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. Interpretation: 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

The role of osmiophilic bodies and Pfg377 expression in female gametocyte emergence and mosquito infectivity in the human malaria parasite <i>Plasmodium falciparum</i>

Osmiophilic bodies are membrane-bound vesicles, found predominantly in Plasmodium female gametocytes, that become progressively more abundant as the gametocyte reaches full maturity. These vesicles lie beneath the subpellicular membrane of the gametocyte, and the release of their contents into the parasitophorous vacuole has been postulated to aid in the escape of gametocytes from the erythrocyte after ingestion by the mosquito. Currently, the only protein known to be associated with osmiophilic bodies in Plasmodium falciparum is Pfg377, a gametocyte-specific protein expressed at the onset of osmiophilic body development. Here we show by targeted gene disruption that Pfg377 plays a fundamental role in the formation of these organelles, and that female gametocytes lacking the full complement of osmiophilic bodies are significantly less efficient both in vitro and in vivo in their emergence from the erythrocytes upon induction of gametogenesis, a process whose timing is critical for fertilization with the short-lived male gamete. This reduced efficiency of emergence explains the significant defect in oocyst formation in mosquitoes fed blood meals containing Pfg377-negative gametocytes, resulting in an almost complete blockade of infectio

How the Reading for Understanding Initiative’s Research Complicates the Simple View of Reading Invoked in the Science of Reading

Advocates of the science of reading have invoked the simple view of reading (SVR) to justify an approach that foregrounds decoding in early reading instruction. The SVR, which describes comprehension as the product of decoding and listening comprehension, also served as the primary theoretical model underlying the Reading for Understanding (RfU) initiative. Research funded under the RfU initiative included direct examinations of the validity of the SVR and the nature of its underlying components and extended the SVR in studies of middle school and high school readers. In this article, the authors use research conducted under the RfU initiative to examine the validity and utility of the SVR, in general, and the appropriateness of its application in the “science of reading” debate. RfU research has provided not only evidence in support of the overall SVR model but also important cautions relevant to the “science of reading” debate. In particular, RfU has provided evidence regarding the significance of the listening comprehension component of the SVR, often overlooked by advocates of the science of reading. This research has documented the importance of early oral language skills, which support both decoding and listening comprehension in young readers and plays a critical role in students’ success as readers as they move through school. In addition, RfU research has identified a complicated constellation of skills and knowledge that impact reading comprehension as students advance in school.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162815/2/rrq343_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162815/1/rrq343.pd