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.

Inhaled Budesonide for COVID-19 in People at Higher Risk of Complications in the Community: The UK National Community Randomi.

Background The effectiveness of repurposed treatments with supportive evidence for higher risk individuals with COVID-19 in the community is unknown. In the UK PRINCIPLE national platform trial we aimed to determine whether 're-purposed medicines' (hydroxychloroquine, azithromycin, doxycycline, colchicine, inhaled budesonide, and other interventions) reduced time to recovery and COVID-19 related hospitalisations/deaths among people at higher risk of COVID-19 complications in the community. We mainly report the findings for budesonide arm here. Methods Participants in this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial were aged ≥65, or ≥50 years with comorbidities, and unwell ≤14 days with suspected COVID-19 in the community, and were randomised to usual care, usual care plus inhaled budesonide (800µg twice daily for 14 days), or usual care plus other interventions. The co-primary endpoints are time to first self-reported recovery, and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Trial registration: ISRCTN86534580. Funded by United Kingdom Research Innovation (MC_PC_19079). Findings The trial opened on April 2, 2020, with the first 4 intervention arms stopped on futility grounds. Randomisation to the budesonide arm occurred from November 27, 2020 until March 31, 2021, when the pre-specified time to recovery superiority criterion was met. The primary analysis model includes 2530 SARS-CoV-2 positive participants, randomised to budesonide (n=787), usual care (n=1069), and other treatments (n=674). Time to first self-reported recovery was shorter in the budesonide group versus usual care (hazard ratio 1·21 [95% credible interval 1·08 to 1·36], probability of superiority >O·999, estimated benefit 2·94 [95% credible interval 1·19 to 5·12] days). An estimated 6·8% COVID-19 related hospitalisations/deaths occurred in the budesonide group versus 8·8% in usual care (estimated absolute difference, 2·0% [95% credible interval -0.2% to 4.5%], probability of superiority 0.963). In the main secondary analysis of admissions using only concurrent controls, admissions occurred in 6.6% (3.8 to 10.1%) in the budesonide group versus 8.8% (95% CI 5.2 to 13.1%), with an absolute difference of 2.2% (0.0 to 4.9%) and a hazard ratio of 0.73 (0.53 to 1.00), meeting the pre-specified superiority probability of 0.975. Three serious adverse events occurred in the budesonide group and three in usual care.

Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.

BACKGROUND: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. METHODS: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 µg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. FINDINGS: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). INTERPRETATION: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications. FUNDING: National Institute of Health Research and United Kingdom Research Innovation.

Primary care preparedness for the SARS-CoV-2 pandemic: a survey of NHS GPs.

BACKGROUND: Primary care manages a significant proportion of healthcare in the United Kingdom and should be a key part of the SARS-CoV-2 pandemic response. AIM: To assess preparedness for the SARS-CoV-2 pandemic by understanding GPs' perception of their ability to manage current and future service demand, set-up of triage processes, and training in Covid-19 infection prevention and control procedures. DESIGN AND SETTING: Cross-sectional survey of practicing GPs in the United Kingdom, with 2 rounds of data collection early in the pandemic. METHODS: Online survey, scripted and hosted by medeConnect Healthcare, comprising 6 closed prompts on 7-point Likert scales, and an optional free-text component. Quantitative data were analysed using descriptive statistics. Free-text data were analysed thematically. RESULTS: One thousand two GPs completed each round; 51 GPs completed free-text responses in March, and 64 in April. Quantitative data showed greatest confidence in triage of Covid-19 patients, and GPs were more confident managing current than future Covid-19 demand. GPs' responses were more optimistic and aligned in April than March. Free-text data highlighted that GPs were concerned about lack of appropriate personal protective equipment and personal risk of Covid-19 infection in March, and unmet needs of non-Covid-19 patients in April. In both rounds, GPs expressed feeling overlooked by government and public health bodies. CONCLUSION: Guidance to support general practice clinicians to manage future waves of Covid-19 or other health emergencies must be tailored to general practice from the outset, to support clinicians to manage competing health demands, and mitigate impacts on primary care providers' wellbeing.

The SARS-CoV-2 pandemic has posed significant challenges for the health services in the United Kingdom and abroad. A Doctors Association UK poll published in early March 2020 found that only 1% of 800 GPs believed the NHS was well prepared for the SARS-CoV-2 pandemic. We surveyed 1,002 GPs across the United Kingdom to gauge how well prepared they felt to cope with the challenges posed by Covid-19. We conducted surveys in March and April 2020, an important time early in the pandemic with rapid changes and uncertainty. We found that GPs were more confident about their ability to manage Covid-19 patients, and do so safely, in April. GPs were most confident that they would be able to triage Covid-19 patients but were concerned about future Covid-19 demand. GPs expressed frustration about a lack of personal protective equipment in March. In April, GPs' primary concern was that patients with other health concerns were not being seen. In both samples, GPs expressed feelings of being overlooked by the government. Primary care needs tailored guidance from as early as possible in a health crisis to support clinicians to manage the competing demands of responding to emergency situations, maintain usual care and their own wellbeing.

Parents' perceptions of antibiotic use and antibiotic resistance (PAUSE): a qualitative interview study.

BACKGROUND: There remains public misconception about antibiotic use and resistance. Preschool children are at particular risk of receiving unnecessary antibiotics because they commonly present in primary care and many childhood infections are self-limiting. OBJECTIVES: The aim of our study was to explore parents' perceptions and understanding of antibiotic use and resistance in the context of their young child with an acute respiratory tract infection (RTI) and to explore strategies parents would find acceptable to minimize antibiotic resistance for their families. METHODS: Semi-structured interviews were conducted with 23 parents of preschool children who recently had an acute RTI across greater Oxfordshire, UK (2016-17 winter). We explored their beliefs about antibiotics, understanding of antibiotic resistance and views on current public antibiotic awareness campaigns at the time. Thematic analysis was used to analyse the data. RESULTS: Parents had a sense of optimism and considered their families to be at low risk of antibiotic resistance because their families were 'low users' of antibiotics. Very few parents considered antibiotic resistance as a possible harm of antibiotics. Parents thought they were acting morally responsibly by following campaign messages. They wanted future campaigns to have a relevant, accessible message for families about the impact of antibiotic resistance. CONCLUSIONS: Future communication about the potential impact of unnecessary antibiotic use and antibiotic resistance needs to focus on outcomes that parents of young children can relate to (e.g. infection recurrence) and in a format that parents will engage with (e.g. face-to-face dissemination at playgroups and parent/child community events) to make a more informed decision about the risks and benefits of antibiotics for their child.

Medications that reduce emergency hospital admissions: an overview of systematic reviews and prioritisation of treatments.

BACKGROUND: Rates of emergency hospitalisations are increasing in many countries, leading to disruption in the quality of care and increases in cost. Therefore, identifying strategies to reduce emergency admission rates is a key priority. There have been large-scale evidence reviews to address this issue; however, there have been no reviews of medication therapies, which have the potential to reduce the use of emergency health-care services. The objectives of this study were to review systematically the evidence to identify medications that affect emergency hospital admissions and prioritise therapies for quality measurement and improvement. METHODS: This was a systematic review of systematic reviews. We searched MEDLINE, PubMed, the Cochrane Database of Systematic Reviews & Database of Abstracts of Reviews of Effects, Google Scholar and the websites of ten major funding agencies and health charities, using broad search criteria. We included systematic reviews of randomised controlled trials that examined the effect of any medication on emergency hospital admissions among adults. We assessed the quality of reviews using AMSTAR. To prioritise therapies, we assessed the quality of trial evidence underpinning meta-analysed effect estimates and cross-referenced the evidence with clinical guidelines. RESULTS: We identified 140 systematic reviews, which included 1968 unique randomised controlled trials and 925,364 patients. Reviews contained 100 medications tested in 47 populations. We identified high-to moderate-quality evidence for 28 medications that reduced admissions. Of these medications, 11 were supported by clinical guidelines in the United States, the United Kingdom and Europe. These 11 therapies were for patients with heart failure (angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, aldosterone receptor antagonists and digoxin), stable coronary artery disease (intensive statin therapy), asthma exacerbations (early inhaled corticosteroids in the emergency department and anticholinergics), chronic obstructive pulmonary disease (long-acting muscarinic antagonists and long-acting beta-2 adrenoceptor agonists) and schizophrenia (second-generation antipsychotics and depot/maintenance antipsychotics). CONCLUSIONS: We identified 11 medications supported by strong evidence and clinical guidelines that could be considered in quality monitoring and improvement strategies to help reduce emergency hospital admission rates. The findings are relevant to health systems with a large burden of chronic disease and those managing increasing pressures on acute health-care services.

Implications of Antibiotic Resistance for Patients' Recovery From Common Infections in the Community: A Systematic Review and Meta-analysis.

BACKGROUND: Antibiotic use is the main driver for carriage of antibiotic-resistant bacteria. The perception exists that failure of antibiotic treatment due to antibiotic resistance has little clinical impact in the community. METHODS: We searched MEDLINE, EMBASE, PubMed, Cochrane Central Register of Controlled Trials, and Web of Science from inception to 15 April 2016 without language restriction. We included studies conducted in community settings that reported patient-level data on laboratory-confirmed infections (respiratory tract, urinary tract, skin or soft tissue), antibiotic resistance, and clinical outcomes. Our primary outcome was clinical response failure. Secondary outcomes were reconsultation, further antibiotic prescriptions, symptom duration, and symptom severity. Where possible, we calculated odds ratios with 95% confidence intervals by performing meta-analysis using random effects models. RESULTS: We included 26 studies (5659 participants). Clinical response failure was significantly more likely in participants with antibiotic-resistant Escherichia coli urinary tract infections (odds ratio [OR] = 4.19; 95% confidence interval [CI] = 3.27-5.37; n = 2432 participants), Streptococcus pneumoniae otitis media (OR = 2.51; 95% CI = 1.29-4.88; n = 921 participants), and S. pneumoniae community-acquired pneumonia (OR = 2.15; 95% CI = 1.32-3.51; n = 916 participants). Clinical heterogeneity precluded primary outcome meta-analysis for Staphylococcus aureus skin or soft-tissue infections. CONCLUSIONS: Antibiotic resistance significantly impacts on patients' illness burden in the community. Patients with laboratory-confirmed antibiotic-resistant urinary and respiratory-tract infections are more likely to experience delays in clinical recovery after treatment with antibiotics. A better grasp of the risk of antibiotic resistance on outcomes that matter to patients should inform more meaningful discussions between healthcare professionals and patients about antibiotic treatment for common infections.

Clinician-targeted interventions to influence antibiotic prescribing behaviour for acute respiratory infections in primary care: an overview of systematic reviews.

BACKGROUND: Antibiotic resistance is a worldwide health threat. Interventions that reduce antibiotic prescribing by clinicians are expected to reduce antibiotic resistance. Disparate interventions to change antibiotic prescribing behaviour for acute respiratory infections (ARIs) have been trialled and meta-analysed, but not yet synthesised in an overview. This overview synthesises evidence from systematic reviews, rather than individual trials. OBJECTIVES: To systematically review the existing evidence from systematic reviews on the effects of interventions aimed at influencing clinician antibiotic prescribing behaviour for ARIs in primary care. METHODS: We searched the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), MEDLINE, Embase, CINAHL, PsycINFO, and Science Citation Index to June 2016. We also searched the reference lists of all included reviews. We ran a pre-publication search in May 2017 and placed additional studies in 'awaiting classification'.We included both Cochrane and non-Cochrane reviews of randomised controlled trials evaluating the effect of any clinician-focussed intervention on antibiotic prescribing behaviour in primary care. Two overview authors independently extracted data and assessed the methodological quality of included reviews using the ROBIS tool, with disagreements reached by consensus or by discussion with a third overview author. We used the GRADE system to assess the quality of evidence in included reviews. The results are presented as a narrative overview. MAIN RESULTS: We included eight reviews in this overview: five Cochrane Reviews (33 included trials) and three non-Cochrane reviews (11 included trials). Three reviews (all Cochrane Reviews) scored low risk across all the ROBIS domains in Phase 2 and low risk of bias overall. The remaining five reviews scored high risk on Domain 4 of Phase 2 because the 'Risk of bias' assessment had not been specifically considered and discussed in the review Results and Conclusions. The trials included in the reviews varied in both size and risk of bias. Interventions were compared to usual care.Moderate-quality evidence indicated that C-reactive protein (CRP) point-of-care testing (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.66 to 0.92, 3284 participants, 6 trials), shared decision making (odds ratio (OR) 0.44, 95% CI 0.26 to 0.75, 3274 participants, 3 trials; RR 0.64, 95% CI 0.49 to 0.84, 4623 participants, 2 trials; risk difference -18.44, 95% CI -27.24 to -9.65, 481,807 participants, 4 trials), and procalcitonin-guided management (adjusted OR 0.10, 95% CI 0.07 to 0.14, 1008 participants, 2 trials) probably reduce antibiotic prescribing in general practice. We found moderate-quality evidence that procalcitonin-guided management probably reduces antibiotic prescribing in emergency departments (adjusted OR 0.34, 95% CI 0.28 to 0.43, 2605 participants, 7 trials). The overall effect of these interventions was small (few achieving greater than 50% reduction in antibiotic prescribing, most about a quarter or less), but likely to be clinically important.Compared to usual care, shared decision making probably makes little or no difference to reconsultation for the same illness (RR 0.87, 95% CI 0.74 to 1.03, 1860 participants, 4 trials, moderate-quality evidence), and may make little or no difference to patient satisfaction (RR 0.86, 95% CI 0.57 to 1.30, 1110 participants, 2 trials, low-quality evidence). Similarly, CRP testing probably has little or no effect on patient satisfaction (RR 0.79, 95% CI 0.57 to 1.08, 689 participants, 2 trials, moderate-quality evidence) or reconsultation (RR 1.08, 95% CI 0.93 to 1.27, 5132 participants, 4 trials, moderate-quality evidence). Procalcitonin-guided management probably results in little or no difference in treatment failure in general practice compared to normal care (adjusted OR 0.95, 95% CI 0.73 to 1.24, 1008 participants, 2 trials, moderate-quality evidence), however it probably reduces treatment failure in the emergency department compared to usual care (adjusted OR 0.76, 95% CI 0.61 to 0.95, 2605 participants, 7 trials, moderate-quality evidence).The quality of evidence for interventions focused on clinician educational materials and decision support in reducing antibiotic prescribing in general practice was either low or very low (no pooled result reported) and trial results were highly heterogeneous, therefore we were unable draw conclusions about the effects of these interventions. The use of rapid viral diagnostics in emergency departments may have little or no effect on antibiotic prescribing (RR 0.86, 95% CI 0.61 to 1.22, 891 participants, 3 trials, low-quality evidence) and may result in little to no difference in reconsultation (RR 0.86, 95% CI 0.59 to 1.25, 200 participants, 1 trial, low-quality evidence).None of the trials in the included reviews reported on management costs for the treatment of an ARI or any associated complications. AUTHORS' CONCLUSIONS: We found evidence that CRP testing, shared decision making, and procalcitonin-guided management reduce antibiotic prescribing for patients with ARIs in primary care. These interventions may therefore reduce overall antibiotic consumption and consequently antibiotic resistance. There do not appear to be negative effects of these interventions on the outcomes of patient satisfaction and reconsultation, although there was limited measurement of these outcomes in the trials. This should be rectified in future trials.We could gather no information about the costs of management, and this along with the paucity of measurements meant that it was difficult to weigh the benefits and costs of implementing these interventions in practice.Most of this research was undertaken in high-income countries, and it may not generalise to other settings. The quality of evidence for the interventions of educational materials and tools for patients and clinicians was either low or very low, which prevented us from drawing any conclusions. High-quality trials are needed to further investigate these interventions.

Chaperones for intimate examinations in family medicine: findings from a pilot study in Melbourne, Australia.

BACKGROUND: The use of medical chaperones during clinical examinations is important whether one practises as a specialist, nurse, medical student or generalist. Chaperone use in general practice remains largely unknown in most countries across the world and, what is known is limited to a handful of countries. Their use in Australian general practice remains unknown. OBJECTIVE: To explore the attitudes and practices of a cohort of general practitioners in urban Melbourne regarding the use of chaperones in their daily clinical practice. METHODS: Self-administered postal questionnaire to pilot group of general practitioners in urban Melbourne, Australia. MAIN OUTCOME MEASURES: Frequency of chaperone use; views on chaperone use itself; preferred choice for the role of chaperone; main reasons for using chaperones. RESULTS: The majority (95% respondents) had never or occasionally used a chaperone. The use of chaperones correlated with general practitioner gender - male general practitioners were more likely to use a chaperone. General practitioners preferred choice as chaperone was the practice nurse. There was no association found between chaperone use and the respondents' age, practice size or the availability of a practice nurse. The most highly rated influence by general practitioners for using a chaperone was because of anticipated patient embarrassment and/or distress. CONCLUSION: This is the first step in understanding attitudes and experiences of general practitioners in general practice in Australia. The results of a larger, national study would provide further insight into this important issue taking into account the realities of general practice in Australia and relationship between general practitioners and patients.

Cost-utility analysis of molnupiravir plus usual care versus usual care alone as early treatment for community-based adults with COVID-19 and increased risk of adverse outcomes in the UK PANORAMIC trial.

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 six months. DESIGN AND SETTING: Economic evaluation of the PANORAMIC trial in the UK. METHOD: A cost-utility analysis that adopted a UK National Health Service and personal social services perspective and a six-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 0.004 to 0.007) than usual care (mean incremental cost per QALY of £81190). Sensitivity and subgroup analyses showed similar results, except those aged ≥75 years with a 55% probability of being cost-effective at a £30000 per QALY threshold. Molnupiravir would have to be priced around £147 per course to be cost-effective at a £15000 per QALY threshold. CONCLUSION: Molnupiravir at the current cost of £513 per course is unlikely to be cost-effective relative to usual care over a six-month time horizon among mainly vaccinated COVID-19 patients at increased risk of adverse outcomes, except those aged ≥75 years.

Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients.

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.

Guidance on C-reactive protein point-of-care testing and complementary strategies to improve antibiotic prescribing for adults with lower respiratory tract infections in primary care.

The world faces the threat of increasing antimicrobial resistance, and there is growing consensus that swift action must be taken to improve the rational use of antibiotics and increase the stewardship of antibiotics to safeguard this key resource in modern healthcare. This paper provides the perspective of an international group of experts on the role of C-reactive protein point-of-care testing (CRP POCT) and other complementary strategies to improve antibiotic stewardship in primary care, with regards to the diagnosis and treatment of adult patients presenting symptoms of lower respiratory tract infections (LRTIs). It provides guidance regarding the clinical assessment of symptoms in combination with C-reactive protein (CRP) results, at the point of care, to support the management decision, and discusses enhanced patient communication and delayed prescribing as complementary strategies to decrease the inappropriate use of antibiotics. Recommendation: CRP POCT should be promoted to improve the identification of adults presenting with symptoms of LRTIs in primary care who might gain additional benefit from antibiotic treatment. Appropriateness of antibiotic use can be maximized when CRP POCT is used together with complementary strategies such as enhanced communication skills training and delayed prescribing in addition to routine safety netting.

C-reactive protein point-of-care testing and complementary strategies to improve antibiotic stewardship in children with acute respiratory infections in primary care.

This paper provides the perspective of an international group of experts on the role of C-reactive protein (CRP) point-of-care testing (POCT) and complementary strategies such as enhanced communication skills training and delayed prescribing to improve antibiotic stewardship in the primary care of children presenting with an acute illness episode due to an acute respiratory tract infection (ARTI). To improve antibiotics prescribing decisions, CRP POCT should be considered to complement the clinical assessment of children (6 months to 14 years) presenting with an ARTI in a primary care setting. CRP POCT can help decide whether a serious infection can be ruled out, before deciding on further treatments or management, when clinical assessment is unconclusive. Based on the evidence currently available, a CRP value can be a valuable support for clinical reasoning and facilitate communication with patients and parents, but the clinical assessment should prevail when making a therapy or referral decision. Nearly half of children tested in the primary care setting can be expected to have a CRP value below 20 mg/l, in which case it is strongly suggested to avoid prescribing antibiotics when the clinical assessment supports ruling out a severe infection. For children with CRP values greater than or equal to 20 mg/l, additional measures such as additional diagnostic tests, observation time, re-assessment by a senior decision-maker, and specialty referrals, should be considered.

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.

Point-of-care diagnostic technology in paediatric ambulatory care: a qualitative interview study of English clinicians and stakeholders.

Point-of-care (POC) tests have the potential to improve paediatric healthcare. However, both the development and evaluation of POC technology have almost solely been focused on adults. We aimed to explore frontline clinicians' and stakeholders' current experience of POC diagnostic technology in children in England; and to identify areas of unmet need. DESIGN, SETTING AND PARTICIPANTS: Qualitative semistructured telephone interviews were carried out with purposively sampled participants from clinical paediatric ambulatory care and charity, industry and policymaking stakeholders. The interviews were audio-recorded, transcribed and analysed thematically. RESULTS: We interviewed 19 clinicians and 8 stakeholders. The main perceived benefits of POC tests and technologies were that they aided early decision-making and could be convenient and empowering when used independently by patients and families. Clinicians and stakeholders wanted more POC tests to be available for use in clinical practice. Most recognised that play and reward are important components of successful POC tests for children. Clinicians wanted tests to give them answers, which would result in a change in their clinical management. Detecting acute serious illness, notably distinguishing viral and bacterial infection, was perceived to be an area where tests could add value. POC tests were thought to be particularly useful for children presenting atypically, where diagnosis was more challenging, such as those less able to communicate, and for rare serious diseases. Many participants felt they could be useful in managing chronic disease. CONCLUSIONS: This exploratory study found that clinicians and stakeholders supported the use of diagnostic POC technology in paediatric ambulatory care settings in England. Some existing tests are not fit for purpose and could be refined. Industry should be encouraged to develop new child-friendly tests tackling areas of unmet need, guided by the preferred characteristics of those working on the ground.

Role of locum GPs in antibiotic prescribing and stewardship: a mixed-methods study.

BACKGROUND: Most antibiotics are prescribed in primary care. Locum or sessional GPs (locums) are perceived as contributing to higher prescribing and may face barriers to engaging with antimicrobial stewardship (AMS). AIM: To identify how locums' antibiotic prescribing compares with other general practice prescribers, and how they perceive their role in antibiotic prescribing and AMS. DESIGN AND SETTING: Mixed-methods study in primary care. METHOD: Data on antibiotic prescribing, diagnoses, and patient and prescriber characteristics were extracted from The Health Improvement Network database. A mixed-effects logistic model was used to compare locums' and other prescribers' antibiotic prescribing for conditions that do not usually benefit from antibiotics. Nineteen semi-structured telephone interviews were conducted with locums in England and analysed thematically. RESULTS: Locums accounted for 11% of consultations analysed. They prescribed antibiotics more often than other GPs and nurse prescribers for acute cough, sore throat, asthma and chronic obstructive pulmonary disease exacerbations, and acute bronchitis. The number of patients receiving antibiotics for these conditions was 4% higher (on absolute scale) when consulting with locums compared with when they consulted with other GPs. Four themes capture the perceived influences on prescribing antibiotics and AMS: antibiotic prescribing as a complex but individual issue, nature and patterns of locum work, relationships between practices and locums, and professional isolation. CONCLUSION: Locums contribute to higher antibiotic prescribing compared with their peers. They experience challenges but also opportunities for contributing to AMS, which should be better addressed. With an increasing proportion of locums in general practice, they have an important role in antibiotic optimisation and AMS.

Colchicine for COVID-19 in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial.

BACKGROUND: Colchicine has been proposed as a COVID-19 treatment. AIM: To determine whether colchicine reduces time to recovery and COVID-19-related admissions to hospital and/or deaths among people in the community. DESIGN AND SETTING: Prospective, multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial (PRINCIPLE). METHOD: Adults aged ≥65 years or ≥18 years with comorbidities or shortness of breath, and unwell for ≤14 days with suspected COVID-19 in the community, were randomised to usual care, usual care plus colchicine (500 µg daily for 14 days), or usual care plus other interventions. The co-primary endpoints were time to first self-reported recovery and admission to hospital/death related to COVID-19, within 28 days, analysed using Bayesian models. RESULTS: The trial opened on 2 April 2020. Randomisation to colchicine started on 4 March 2021 and stopped on 26 May 2021 because the prespecified time to recovery futility criterion was met. The primary analysis model included 2755 participants who were SARS-CoV-2 positive, randomised to colchicine (n = 156), usual care (n = 1145), and other treatments (n = 1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.92 (95% credible interval (CrI) = 0.72 to 1.16) and an estimated increase of 1.4 days in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. COVID-19-related admissions to hospital/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 (95% CrI = 0.28 to 1.89) and an estimated difference of -0.4% (95% CrI = -2.7 to 2.4). CONCLUSION: Colchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community.

Polymyalgia rheumatica -- diagnosis and management.

BACKGROUND: Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease and an indication for long term treatment with oral steroids. Its incidence rises progressively beyond the age of 50 years. For the most part, PMR is managed in primary care. OBJECTIVE: This article highlights the main points in the British Society for Rheumatology and the British Health Professionals in Rheumatology guidelines that may be useful to general practitioners in the primary care setting. DISCUSSION: Different levels of awareness of the condition between practitioners, and a lack of uniform diagnostic criteria may impede correct diagnosis and management of PMR. Updated international guidelines produced by the British Society for Rheumatology and the British Health Professionals in Rheumatology can aid diagnosis and direct treatment and disease monitoring.

Exploring Primary Care Clinicians' Views about How Best to Implement a Potential Trial around Point-of-Care Tests for Common Infections in South Africa.

Optimisation of antibiotic prescribing is critical to combat antimicrobial resistance. Point-of-care tests (POCTs) for common infections could be a valuable tool to achieve this in primary care. Currently, their use has primarily been studied in high-income countries. Trials in low-and-middle-income countries face challenges unique to their setting. This study aims to explore the barriers and facilitators for a future trial of POCTs for common infections in South Africa. Twenty-three primary care clinicians in the Western Cape Metropole were interviewed. Interview transcripts were analysed using thematic analysis. We identified three key themes. These themes focused on clinicians' views about proposed trial design and novel POCTs, clinicians' perspectives about trial set-up, and specific trial procedures. Participants were overall positive about the proposed trial and POCTs. Potential issues centred around the limited space and technology available and participant retention to follow-up. Additionally, impact on clinic workload was an important consideration. These insights will be invaluable in informing the design of a feasibility trial of POCTs in this setting.