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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. FUNDING: UK Research and Innovation and National Institute for Health and Care Research.

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BACKGROUND: The cost-effectiveness of molnupiravir, an oral antiviral for early treatment of SARS-CoV-2, has not been established in vaccinated populations. AIM: To evaluate the cost-effectiveness of molnupiravir relative to usual care alone among mainly vaccinated community-based people at higher risk of severe outcomes from COVID-19 over 6 months. DESIGN AND SETTING: An economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK NHS and personal social services perspective and a 6-month time horizon was performed using PANORAMIC trial data. Cost-effectiveness was expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Sensitivity and subgroup analyses assessed the impacts of uncertainty and heterogeneity. Threshold analysis explored the price for molnupiravir consistent with likely reimbursement. RESULTS: In the base-case analysis, molnupiravir had higher mean costs of £449 (95% confidence interval [CI] = 445 to 453) and higher mean QALYs of 0.0055 (95% CI = 0.0044 to 0.0067) than usual care (mean incremental cost per QALY of £81 190). Sensitivity and subgroup analyses showed similar results, except for those aged ≥75 years, with a 55% probability of being cost-effective at a £30 000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15 000 per QALY threshold. CONCLUSION: At the current cost of £513 per course, molnupiravir is unlikely to be cost-effective relative to usual care over a 6-month time horizon among mainly vaccinated patients with COVID-19 at increased risk of adverse outcomes, except those aged ≥75 years.

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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.

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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.

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OBJECTIVE: To evaluate the impact of congenital heart diseases in growth of children with Down syndrome (DS) and the weight-height recovery after surgical correction. METHODS: Retrospective study of the DS patients between 1984 and 2007. Excluding the mosaics and/or patients with associated morbidities (n=165). Calculated Z scores for weight (Zwb) and length (Zlb) at birth. Those patients submitted to surgical correction (n= 60) these scores (Zw/Zh) were evaluated before surgery and in subsequent periods to five years. Malnutrition was defined as weight/height Z-score < 2.5. Used Chi-square test to verify the relation between weight/length and age at the time of surgery and Student T test to evaluate the postoperative (PO) time of recovery (P < 0.05). RESULTS: Means Zwb (n = 162) and Zlb (n = 156) were -0.95 ± 1.27 and -1.348 ± 1.02. From the total data (n = 165), 65.5% (n = 108) presented heart disease. Those submitted to cardiac surgery (n = 60), Zw was below -2.5 in 55% (n = 33) and Zh in 60% (n = 36). After six months PO, 67.4% achieved Zw > 2.5. In one year, 85.7% achieved Zh > 2.5. Dividing this group by age in tertiles at time of surgery no difference was found. CONCLUSIONS: We concluded that malnutrition common in children with DS since birth. DS children with congenital heart and surgical indication were smaller and lighter than those without or with mild disease. PO recovery occurred in 6 months for weight and one year for height, with no difference in the age at the time of surgery.

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OBJETIVO: Revisar, de forma sistemática, as curvas de crescimento de crianças e adolescentes com síndrome de Down de diferentes países publicadas entre 1978 e 2008. FONTES DOS DADOS: Revisão sistemática baseada em dados eletrônicos (Medline, Lilacs e algumas referências de artigos citados), sendo selecionados títulos científicos publicados no intervalo de 30 anos. Analisadas as principais características dessas curvas de crescimento nos diferentes países. Excluídos estudos exclusivos de perímetro cefálico e os que não incluíam a construção de curvas de peso e/ ou estatura na síndrome de Down. As variáveis de peso e estatura/comprimento foram expressas em kg, centímetros e/ou escores Z. SÍNTESE DOS DADOS: Baixo peso e comprimento ao nascimento, baixa estatura final, prevalência de sobrepeso/ obesidade e reduzida velocidade de crescimento são caracte-rísticas importantes do crescimento na síndrome de Down. Cardiopatias congênitas e outras comorbidades podem ocorrer na síndrome, contribuindo para comprometer mais o crescimento deficiente. Nos estudos revisados, a média de estatura final variou entre 141,9 e 155cm para o gênero feminino e entre 150 e 165cm para o masculino (desvio padrão: -2,0 a -4,0). CONCLUSÕES: Reduzida velocidade de crescimento esta-tural, baixa estatura final e crescimento puberal total mais curto e precoce foram observados. Após o final da infância, ocorreu prevalência de sobrepeso/obesidade. É importante o uso de curvas específicas para a síndrome de Down para o reconhecimento precoce e adequado de doenças adicionais e/ou de sobrepeso/obesidade incipiente.

OBJECTIVE: To systematic review studies of growth charts in children and teenagers with Down syndrome from differ-ent countries published between 1978 and 2008. DATA SOURCES: Electronic databases (Medline, Lilacs) and references of the selected citations of papers published be-tween 1972-2008. The growth charts of Down syndrome in different countries were analyzed. Studies related only to head circumference charts and Down syndrome growth studies without curves were excluded. In order to describe the variables of weight and length, kilograms, centimeters and Z scores were used. DATA SYNTHESIS: Lower birth length and weight, final short stature, higher prevalence of overweight/obesity in late childhood/adolescence (about 30 percent) and a reduced growth velocity are cardinal features of growth in Down syndrome. Congenital heart defects and other major dis-eases frequently occur and are possible causes of growth delay. Individual mean final height varied between 141.9 to 155cm for girls and 150 to165cm for boys (-2.0 to -4.0 standard deviations). CONCLUSIONS: A delay in growth velocity, a shorter fi-nal stature and a shorter and earlier pubertal growth were observed in this review. There was a higher prevalence of overweight/obesity after late childhood. The use of specific growth charts can help the early recognition of additional diseases and/or incipient obesity/overweight in patients with Down syndrome.

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OBJETIVO: Avaliar o impacto das cardiopatias congênitas em crianças no crescimento de crianças com síndrome de Down (SD) e a sua recuperação pôndero-estatural após correção cirúrgica. MÉTODOS: Estudo retrospectivo de portadores da SD, entre 1984 e 2007. Excluídos os mosaicos e/ou portadores de morbidades associadas (n=165). Calcularam-se os escores Z para peso (Zpn) e comprimento (Zen) no momento do nascimento. Nos pacientes submetidos à correção cirúrgica (n=60), os escores Zp e Ze foram calculados antes da intervenção cirúrgica e em períodos posteriores, em até cinco anos de pós-operatório (PO). Em relação à população geral, Zp e Ze < 2,5 foram significativos para déficit de crescimento. Utilizado teste do Qui-Quadrado para verificar relação entre peso/estatura e idade no momento da cirurgia e teste T de Student para avaliar o momento em que ocorreu a recuperação PO (P < 0,05). RESULTADOS: As médias de Zpn (n=162) e Zen (n=156) foram -0,95 ± 1,27 e -1,348 ± 1,02. Da amostra total (n=165), 65,5% (n=108) dos pacientes apresentavam doença cardíaca. Dentre os pacientes submetidos (n=60) à cirurgia cardíaca, Zp era inferior a -2,5 em 55% (n=33) e Ze, em 60% (n=36). Com seis meses de PO, 67,4% alcançaram Zp > 2,5. Em um ano, 85,7% atingiram Ze > 2,5. Dividindo este grupo por idade, na época da cirurgia, em tercis não ocorreu diferença. CONCLUSÕES: Observou-se déficit pôndero-estatural em relação à população geral desde o nascimento, sendo maior nas crianças com cardiopatia de indicação cirúrgica. A recuperação PO ocorreu em seis meses para o peso e em um ano para a estatura, sem diferença quanto à idade no momento cirúrgico.

OBJECTIVE: To evaluate the impact of congenital heart diseases in growth of children with Down syndrome (DS) and the weight-height recovery after surgical correction. METHODS: Retrospective study of the DS patients between 1984 and 2007. Excluding the mosaics and/or patients with associated morbidities (n=165). Calculated Z scores for weight (Zwb) and length (Zlb) at birth. Those patients submitted to surgical correction (n= 60) these scores (Zw/Zh) were evaluated before surgery and in subsequent periods to five years. Malnutrition was defined as weight/height Z-score < 2.5. Used Chi-square test to verify the relation between weight/length and age at the time of surgery and Student T test to evaluate the postoperative (PO) time of recovery (P < 0.05). RESULTS: Means Zwb (n = 162) and Zlb (n = 156) were -0.95 ± 1.27 and -1.348 ± 1.02. From the total data (n = 165), 65.5% (n = 108) presented heart disease. Those submitted to cardiac surgery (n = 60), Zw was below -2.5 in 55% (n = 33) and Zh in 60% (n = 36). After six months PO, 67.4% achieved Zw > 2.5. In one year, 85.7% achieved Zh > 2.5. Dividing this group by age in tertiles at time of surgery no difference was found. CONCLUSIONS: We concluded that malnutrition common in children with DS since birth. DS children with congenital heart and surgical indication were smaller and lighter than those without or with mild disease. PO recovery occurred in 6 months for weight and one year for height, with no difference in the age at the time of surgery.

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Os autores relatam o caso de paciente que, após realizaçäo de biópsia renal percutânea, evoluiu com fístula artério-venosa e hipertensäo arterial sistêmica

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