Lack of evidence for interventions offered in UK fertility centres.

Carl Heneghan and colleagues call for better quality evidence to help people seeking assisted reproduction make informed choices

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

This is the author accepted manuscript. The final version is available on open access from the Royal College of General Practitioners via the DOI in this recordData availability: Qualifying researchers who wish to access our data should submit a proposal with a valuable research question. Proposals will be assessed by a committee formed from the trial management group, including senior statistical and clinical representation. Data will be shared in accordance with the data sharing policy of Nuffield Department of Primary Care Health Sciences.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.National Institute for Health and Care Research (NIHR

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

This is the final version. Available on open access from Elsevier via the DOI in this recordData sharing: Qualifying researchers who wish to access our data should submit a proposal with a valuable research question. Proposals will be assessed by a committee formed from the trial management group, including senior statistical and clinical representation. Data will be shared in accordance with the data sharing policy of Nuffield Department of Primary Care Health Sciences.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.National Institute for Health Research (NIHR

A core outcome set for pre‐eclampsia research: an international consensus development study

Objective To develop a core outcome set for pre‐eclampsia. Design Consensus development study. Setting International. Population Two hundred and eight‐one healthcare professionals, 41 researchers and 110 patients, representing 56 countries, participated. Methods Modified Delphi method and Modified Nominal Group Technique. Results A long‐list of 116 potential core outcomes was developed by combining the outcomes reported in 79 pre‐eclampsia trials with those derived from thematic analysis of 30 in‐depth interviews of women with lived experience of pre‐eclampsia. Forty‐seven consensus outcomes were identified from the Delphi process following which 14 maternal and eight offspring core outcomes were agreed at the consensus development meeting. Maternal core outcomes: death, eclampsia, stroke, cortical blindness, retinal detachment, pulmonary oedema, acute kidney injury, liver haematoma or rupture, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, admission to intensive care required, and intubation and ventilation. Offspring core outcomes: stillbirth, gestational age at delivery, birthweight, small‐for‐gestational‐age, neonatal mortality, seizures, admission to neonatal unit required and respiratory support. Conclusions The core outcome set for pre‐eclampsia should underpin future randomised trials and systematic reviews. Such implementation should ensure that future research holds the necessary reach and relevance to inform clinical practice, enhance women's care and improve the outcomes of pregnant women and their babies

Cranberry extract for symptoms of acute, uncomplicated urinary tract infection

Background There is growing interest in using non-antibiotic treatments for common bacterial infections, such as Urinary Tract Infections (UTI). One potential non-antibiotic treatment for acute uncomplicated UTI is cranberry extract. Methods The existing evidence for using cranberry extract to treat acute, uncomplicated UTIs was systematically reviewed. An open-label, randomised feasibility trial was conducted to determine the feasibility of trialling cranberry extract as a treatment for symptoms of acute, uncomplicated UTI in primary care. Adult women with acute UTI symptoms were randomly assigned to one of three groups: 1) Immediate antibiotic prescription (controls) 2) Immediate antibiotic prescription and immediate cranberry capsules 3) Immediate cranberry capsules and a delayed antibiotic prescription. Two qualitative studies were embedded within the feasibility trial: The first was conducted with UTI patients (both participants and non-participants of the feasibility trial); and the second was conducted with feasibility trial recruiters. Results The systematic review found that the evidence base for or against using cranberry extract for treating acute UTIs was limited. Four General Practices (100% of target) recruited to the feasibility trial, with nine participants recruited per month on average. Forty-six participants were recruited (one beyond target). 89.1% (41/46) of electronic symptom diaries contained some participant entered data, and 69.6% (32/46) were fully completed. Interviewed UTI patients (n=26) and recruiters (n=8) felt that the feasibility trial addressed an important question, and generally found trial processes straightforward. Many UTI patients indicated that they would be happy to delay antibiotic treatment and try initial symptomatic treatment, such as cranberry extract, for acute UTI symptoms in certain circumstances (e.g. with milder symptoms). Conclusions The safety and effectiveness of using cranberry extract as a treatment for acute, uncomplicated UTIs represents an evidence gap. The present research programme demonstrates that it is feasible and acceptable to UTI patients to trial cranberry extract for managing symptoms of acute, uncomplicated UTIs. Having established the feasibility of this approach, an adequately powered efficacy trial of cranberry extract for acute UTI is indicated.</p

Evidence for the effectiveness of pomegranate supplementation for blood pressure management is weak: A systematic review of randomized clinical trials

Hypertension is one of the most important preventable causes of premature death. Studies have been conducted assessing the impact of pomegranate on blood pressure, with varying results. The aim of this review was to critically appraise and evaluate the effect of pomegranate on blood pressure in adults, using evidence from randomized clinical trials (RCTs). We conducted electronic searches in Medline, Embase, Amed, and The Cochrane Library, and included RCTs assessing the effectiveness of pomegranate on blood pressure. We assessed the reporting quality using the Cochrane criteria. We included 8 RCTs comprising 619 participants. The studies varied in their reporting quality, and compared pomegranate juice or capsules with a control. Two studies reported significant reductions in systolic blood pressure favoring pomegranate: p = .002 and p &lt; .001 respectively; 3 studies reported no significant differences between groups; and 3 studies failed to report between-group differences. Two studies reported significant reductions in diastolic blood pressure favoring pomegranate: p = .038, p &lt; .001, respectively; 4 studies reported no significant between-group differences; and 2 studies did not report between group differences. No adverse events were observed. The limited evidence from clinical trials to date fails to convincingly show a beneficial effect of pomegranate on blood pressure. We have identified evidence gaps and highlight areas for future research to be conducted, including performing studies of high quality and longer duration

Diagnostic value of symptoms and signs for identifying urinary tract infection in older adult outpatients: systematic review and meta-analysis

Objectives To critically appraise and evaluate the diagnostic value of symptoms and signs in identifying UTI in older adult outpatients, using evidence from observational studies. Methods We searched Medline and Medline in process, Embase and Web of Science, from inception up to September 2017. We included studies assessing the diagnostic accuracy of symptoms and/or signs in predicting UTI in outpatients aged 65 years and above. Study quality was assessed using the QUADAS-2 tool. Results We identified 15 eligible studies of variable quality, with a total of 12,039 participants (range 65–4259), and assessed the diagnostic accuracy of 66 different symptoms and signs in predicting UTI. A number of symptoms and signs typically associated with UTI, such as nocturia, urgency and abnormal vital signs, were of limited use in older adult outpatients. Inability to perform a number of acts of daily living were predictors of UTI: For example, disability in feeding oneself, + ve LR: 11.8 (95% CI 5.51–25.2) and disability in washing one's hands and face, + ve LR: 6.84 (95% CI 4.08–11.5). Conclusions The limited evidence of varying quality shows that a number of symptoms and signs traditionally associated with UTI may have limited diagnostic value in older adult outpatients

Diagnostic value of symptoms and signs for identifying urinary tract infection in older adult outpatients: systematic review and meta-analysis

Objectives To critically appraise and evaluate the diagnostic value of symptoms and signs in identifying UTI in older adult outpatients, using evidence from observational studies. Methods We searched Medline and Medline in process, Embase and Web of Science, from inception up to September 2017. We included studies assessing the diagnostic accuracy of symptoms and/or signs in predicting UTI in outpatients aged 65 years and above. Study quality was assessed using the QUADAS-2 tool. Results We identified 15 eligible studies of variable quality, with a total of 12,039 participants (range 65–4259), and assessed the diagnostic accuracy of 66 different symptoms and signs in predicting UTI. A number of symptoms and signs typically associated with UTI, such as nocturia, urgency and abnormal vital signs, were of limited use in older adult outpatients. Inability to perform a number of acts of daily living were predictors of UTI: For example, disability in feeding oneself, + ve LR: 11.8 (95% CI 5.51–25.2) and disability in washing one's hands and face, + ve LR: 6.84 (95% CI 4.08–11.5). Conclusions The limited evidence of varying quality shows that a number of symptoms and signs traditionally associated with UTI may have limited diagnostic value in older adult outpatients

Biomarkers for diagnosing serious bacterial infections in older outpatients: a systematic review

Background The value of biomarkers for diagnosing bacterial infections in older outpatients is uncertain and limited official guidance exists for clinicians in this area. The aim of this review is to critically appraise and evaluate biomarkers for diagnosing bacterial infections in older adults (aged 65 years and above). Methods We searched Medline, Embase, Web of Science and the Cochrane Library, from inception to January 2018. We included studies assessing the diagnostic accuracy of blood, urinary, and salivary biomarkers in diagnosing bacterial infections in older adults. The QUADAS-2 tool was used to assess study quality. Results We identified 11 eligible studies of moderate quality (11,034 participants) including 51 biomarkers at varying thresholds for diagnosing bacterial infections. An elevated Procalcitonin (≥ 0.2 ng/mL) may help diagnose bacteraemia in older adults [+ve LR range 1.50 to 2.60]. A CRP ≥ 50 mg/L only raises the probability of bacteraemia by 5%. A positive urine dipstick aids diagnosis of UTI (+ve LR range 1.23 to 54.90), and absence helps rule out UTI (−ve LR range 0.06 to 0.46). An elevated white blood cell count is unhelpful in diagnosing intra-abdominal infections (+ve LR range 0.75 to 2.62), but may aid differentiation of bacterial infection from other acute illness (+ve LR range 2.14 to 7.12). Conclusions The limited available evidence suggests that many diagnostic tests useful in younger patients, do not help to diagnose bacterial infections in older adults. Further evidence from high quality studies is urgently needed to guide clinical practice. Until then, symptoms and signs remain the mainstay of diagnosis in community based populations

Lack of evidence for interventions offered in UK fertility centres

Carl Heneghan and colleagues call for better quality evidence to help people seeking assisted reproduction make informed choices