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.

Use of the FebriDx® host-response point-of-care test may reduce antibiotic use for respiratory tract infections in primary care: a mixed-methods feasibility study.

INTRODUCTION: FebriDx® is a CE-marked, single-use point-of-care test with markers for bacterial [C-reactive protein (CRP)] and viral [myxovirus resistance protein A (MxA)] infection, using finger-prick blood samples. Results are available after 10-12 min. We explored the usability and potential impact of FebriDx® in reducing antibiotic prescriptions for lower respiratory tract infection (LRTI) in primary care, and the feasibility of conducting a randomized controlled trial (RCT). METHODS: Patients (aged ≥1 year) with LRTI deemed likely to receive antibiotic prescription were recruited at nine general practices and underwent FebriDx® testing. Data collection included FebriDx® results, antibiotic prescribing plan (before and after testing) and re-consultation rates. Staff completed System Usability Scale questionnaires. RESULTS: From 31 January 2023 to 9 June 2023, 162 participants participated (median age 57 years), with a median symptom duration of 7 days (IQR 5-14). A valid FebriDx® result was obtained in 97% (157/162). Of 155 patients with available results, 103 (66%) had no detectable CRP or MxA, 28 (18%) had CRP only, 5 (3%) had MxA only, and 19 (12%) had both CRP and MxA. The clinicians' stated management plan was to prescribe antibiotics for 86% (134/155) before testing and 45% (69/155) after testing, meaning a 41% (95% CI: 31%, 51%) difference after testing, without evidence of increased re-consultation rates. Ease-of-use questionnaires showed 'good' user-friendliness. CONCLUSIONS: Use of FebriDx® to guide antibiotic prescribing for LRTI in primary care was associated with a substantial reduction in prescribing intentions. These results support a fully powered RCT to confirm its impact and safety.

Systemic antibiotics for symptomatic apical periodontitis and acute apical abscess in adults.

BACKGROUND: Dental pain can have a detrimental effect on quality of life. Symptomatic apical periodontitis and acute apical abscess are common causes of dental pain and arise from an inflamed or necrotic dental pulp, or infection of the pulpless root canal system. Clinical guidelines recommend that the first-line treatment for these conditions should be removal of the source of inflammation or infection by local operative measures, and that systemic antibiotics are currently only recommended for situations where there is evidence of spreading infection (cellulitis, lymph node involvement, diffuse swelling) or systemic involvement (fever, malaise). Despite this, there is evidence that dentists frequently prescribe antibiotics in the absence of these signs. There is concern that this could contribute to the development of antibiotic-resistant bacteria. This review is the second update of the original version first published in 2014. OBJECTIVES: To evaluate the effects of systemic antibiotics provided with or without surgical intervention (such as extraction, incision and drainage of a swelling, or endodontic treatment), with or without analgesics, for symptomatic apical periodontitis and acute apical abscess in adults. SEARCH METHODS: We searched Cochrane Oral Health's Trials Register (26 February 2018 (discontinued)), CENTRAL (2022, Issue 10), MEDLINE Ovid (23 November 2022), Embase Ovid (23 November 2022), CINAHL EBSCO (25 November 2022) and two trials registries, and performed a grey literature search. There were no restrictions on language or date of publication. SELECTION CRITERIA: Randomised controlled trials of systemic antibiotics in adults with a clinical diagnosis of symptomatic apical periodontitis or acute apical abscess, with or without surgical intervention (considered in this situation to be extraction, incision and drainage, or endodontic treatment) and with or without analgesics. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the searches against inclusion criteria, extracted data and assessed risk of bias. We used a fixed-effect model in the meta-analysis as there were fewer than four studies. We contacted study authors to request missing information. We used GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: There was one new completed trial on this topic since the last update in 2018. In total, we included three trials with 134 participants. Systemic antibiotics versus placebo with surgical intervention and analgesics for symptomatic apical periodontitis or acute apical abscess One trial (72 participants) compared the effects of a single preoperative dose of clindamycin versus a matched placebo when provided with a surgical intervention (endodontic chemo-mechanical debridement and filling) and analgesics to adults with symptomatic apical periodontitis. We assessed this study at low risk of bias. There were no differences in participant-reported pain or swelling across trial arms at any time point assessed. The median values for pain (numerical rating scale 0 to 10) were 3.0 in both groups at 24 hours (P = 0.219); 1.0 in the antibiotic group versus 2.0 in the control group at 48 hours (P = 0.242); and 0 in both groups at 72 hours and seven days (P = 0.116 and 0.673, respectively). The risk ratio of swelling when comparing preoperative antibiotic to placebo was 0.50 (95% confidence interval (CI) 0.10 to 2.56; P = 0.41). The certainty of evidence for all outcomes in this comparison was low. Two trials (62 participants) compared the effects of a seven-day course of oral phenoxymethylpenicillin (penicillin VK) versus a matched placebo when provided with a surgical intervention (total or partial endodontic chemo-mechanical debridement) and analgesics to adults with acute apical abscess or symptomatic necrotic tooth. Participants in both trials also received oral analgesics. We assessed one study at high risk of bias and the other at unclear risk of bias. There were no differences in participant-reported pain or swelling at any time point assessed. The mean difference for pain (short ordinal numerical scale 0 to 3, where 0 was no pain) was -0.03 (95% CI -0.53 to 0.47) at 24 hours; 0.32 (95% CI -0.22 to 0.86) at 48 hours; and 0.08 (95% CI -0.38 to 0.54) at 72 hours. The standardised mean difference for swelling was 0.27 (95% CI -0.23 to 0.78) at 24 hours; 0.04 (95% CI -0.47 to 0.55) at 48 hours; and 0.02 (95% CI -0.49 to 0.52) at 72 hours. The certainty of evidence for all the outcomes in this comparison was very low. Adverse effects, as reported in two studies, were diarrhoea (one participant in the placebo group), fatigue and reduced energy postoperatively (one participant in the antibiotic group) and dizziness preoperatively (one participant in the antibiotic group). Systemic antibiotics without surgical intervention for adults with symptomatic apical periodontitis or acute apical abscess We found no studies that compared the effects of systemic antibiotics with a matched placebo delivered without a surgical intervention for symptomatic apical periodontitis or acute apical abscess in adults. AUTHORS' CONCLUSIONS: The evidence suggests that preoperative clindamycin for adults with symptomatic apical periodontitis results in little to no difference in participant-reported pain or swelling at any of the time points included in this review when provided with chemo-mechanical endodontic debridement and filling under local anaesthesia. The evidence is very uncertain about the effect of postoperative phenoxymethylpenicillin for adults with localised apical abscess or a symptomatic necrotic tooth when provided with chemo-mechanical debridement and oral analgesics. We found no studies which compared the effects of systemic antibiotics with a matched placebo delivered without a surgical intervention for symptomatic apical periodontitis or acute apical abscess in adults.

Correction: Internet Tool to Support Self-Assessment and Self-Swabbing of Sore Throat: Development and Feasibility Study.

[This corrects the article DOI: 10.2196/39791.].

Long-term oral antibiotic use in people with acne vulgaris in UK primary care: a drug utilization study.

BACKGROUND: The inappropriate use of antibiotics is understood to contribute to antimicrobial resistance. Oral antibiotics are regularly used to treat moderate-to-severe acne vulgaris. In practice, we do not know the typical length of oral antibiotic treatment courses for acne in routine primary care and what proportion of people receive more than one course of treatment following a new acne diagnosis. OBJECTIVES: To describe how oral antibiotics are prescribed for acne over time in UK primary care. METHODS: We conducted a descriptive longitudinal drug utilization study using routinely collected primary care data from the Clinical Practice Research Datalink GOLD (2004-2019). We included individuals (8-50 years) with a new acne diagnosis recorded between 1 January 2004 and 31 July 2019. RESULTS: We identified 217 410 people with a new acne diagnosis. The median age was 17 years [interquartile range (IQR) 15-25] and median follow-up was 4.3 years (IQR 1.9-7.6). Among people with a new acne diagnosis, 96 703 (44.5%) received 248 560 prescriptions for long-term oral antibiotics during a median follow-up of 5.3 years (IQR 2.8-8.5). The median number of continuous courses of antibiotic therapy (≥ 28 days) per person was four (IQR 2-6). The majority (n = 59 010, 61.0%) of first oral antibiotic prescriptions in those with a recorded acne diagnosis were between the ages of 12 and 18. Most (n = 71 544, 74.0%) first courses for oral antibiotics were for between 28 and 90 days. The median duration of the first course of treatment was 56 days (IQR 50-93 days) and 18 127 (18.7%) of prescriptions of ≥ 28 days were for < 6 weeks. Among people who received a first course of oral antibiotic for ≥ 28 days, 56 261 (58.2%) received a second course after a treatment gap of ≥ 28 days. The median time between first and second courses was 135 days (IQR 67-302). The cumulative duration of exposure to oral antibiotics during follow-up was 255 days (8.5 months). CONCLUSIONS: Further work is needed to understand the consequences of using antibiotics for shorter periods than recommended. Suboptimal treatment duration may result in reduced clinical effectiveness or repeated exposures, potentially contributing to antimicrobial resistance.

Non-pharmaceutical interventions and risk of COVID-19 infection: survey of U.K. public from November 2020 - May 2021.

INTRODUCTION: Non-pharmaceutical interventions (NPIs), such as handwashing, social distancing and face mask wearing, have been widely promoted to reduce the spread of COVID-19. This study aimed to explore the relationship between self-reported use of NPIs and COVID-19 infection. METHODS: We conducted an online questionnaire study recruiting members of the UK public from November 2020 to May 2021. The association between self-reported COVID-19 illness and reported use of NPIs was explored using logistic regression and controlling for participant characteristics, month of questionnaire completion, and vaccine status. Participants who had been exposed to COVID-19 in their household in the previous 2 weeks were excluded. RESULTS: Twenty-seven thousand seven hundred fifty-eight participants were included and 2,814 (10.1%) reported having a COVID-19 infection. The odds of COVID-19 infection were reduced with use of a face covering in unadjusted (OR 0.17 (95% CI: 0.15 to 0.20) and adjusted (aOR 0.19, 95% CI 0.16 to 0.23) analyses. Social distancing (OR 0.27, 95% CI: 0.22 to 0.31; aOR 0.35, 95% CI 0.28 to 0.43) and handwashing when arriving home (OR 0.57, 95% CI 0.46 to 0.73; aOR 0.63, 95% CI: 0.48 to 0.83) also reduced the odds of COVID-19. Being in crowded places of 10-100 people (OR 1.89, 95% CI: 1.70 to 2.11; aOR 1.62, 95% CI: 1.42 to 1.85) and > 100 people (OR 2.33, 95% CI: 2.11 to 2.58; aOR 1.73, 95% CI: 1.53 to 1.97) were both associated with increased odds of COVID-19 infection. Handwashing before eating, avoiding touching the face, and cleaning things with virus on were all associated with increased odds of COVID-19 infections. CONCLUSIONS: This large observational study found evidence for strong protective effects for individuals from use of face coverings, social distancing (including avoiding crowded places) and handwashing on arriving home on developing COVID-19 infection. We also found evidence for an increased risk associated with other behaviours, possibly from recall bias.

Internet Tool to Support Self-Assessment and Self-Swabbing of Sore Throat: Development and Feasibility Study.

BACKGROUND: Sore throat is a common problem and a common reason for the overuse of antibiotics. A web-based tool that helps people assess their sore throat, through the use of clinical prediction rules, taking throat swabs or saliva samples, and taking throat photographs, has the potential to improve self-management and help identify those who are the most and least likely to benefit from antibiotics. OBJECTIVE: We aimed to develop a web-based tool to help patients and parents or carers self-assess sore throat symptoms and take throat photographs, swabs, and saliva samples for diagnostic testing. We then explored the acceptability and feasibility of using the tool in adults and children with sore throats. METHODS: We used the Person-Based Approach to develop a web-based tool and then recruited adults and children with sore throats who participated in this study by attending general practices or through social media advertising. Participants self-assessed the presence of FeverPAIN and Centor score criteria and attempted to photograph their throat and take throat swabs and saliva tests. Study processes were observed via video call, and participants were interviewed about their views on using the web-based tool. Self-assessed throat inflammation and pus were compared to clinician evaluation of patients' throat photographs. RESULTS: A total of 45 participants (33 adults and 12 children) were recruited. Of these, 35 (78%) and 32 (71%) participants completed all scoring elements for FeverPAIN and Centor scores, respectively, and most (30/45, 67%) of them reported finding self-assessment relatively easy. No valid response was provided for swollen lymph nodes, throat inflammation, and pus on the throat by 11 (24%), 9 (20%), and 13 (29%) participants respectively. A total of 18 (40%) participants provided a throat photograph of adequate quality for clinical assessment. Patient assessment of inflammation had a sensitivity of 100% (3/3) and specificity of 47% (7/15) compared with the clinician-assessed photographs. For pus on the throat, the sensitivity was 100% (3/3) and the specificity was 71% (10/14). A total of 89% (40/45), 93% (42/45), 89% (40/45), and 80% (30/45) of participants provided analyzable bacterial swabs, viral swabs, saliva sponges, and saliva drool samples, respectively. Participants were generally happy and confident in providing samples, with saliva samples rated as slightly more acceptable than swab samples. CONCLUSIONS: Most adult and parent participants were able to use a web-based intervention to assess the clinical features of throat infections and generate scores using clinical prediction rules. However, some had difficulties assessing clinical signs, such as lymph nodes, throat pus, and inflammation, and scores were assessed as sensitive but not specific. Many participants had problems taking photographs of adequate quality, but most were able to take throat swabs and saliva samples.

Antibiotics for lower respiratory tract infection in children presenting in primary care in England (ARTIC PC): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Antibiotic resistance is a global public health threat. Antibiotics are very commonly prescribed for children presenting with uncomplicated lower respiratory tract infections (LRTIs), but there is little evidence from randomised controlled trials of the effectiveness of antibiotics, both overall or among key clinical subgroups. In ARTIC PC, we assessed whether amoxicillin reduces the duration of moderately bad symptoms in children presenting with uncomplicated (non-pneumonic) LRTI in primary care, overall and in key clinical subgroups. METHODS: ARTIC PC was a double-blind, randomised, placebo-controlled trial done at 56 general practices in England. Eligible children were those aged 6 months to 12 years presenting in primary care with acute uncomplicated LRTI judged to be infective in origin, where pneumonia was not suspected clinically, with symptoms for less than 21 days. Patients were randomly assigned in a 1:1 ratio to receive amoxicillin 50 mg/kg per day or placebo oral suspension, in three divided doses orally for 7 days. Patients and investigators were masked to treatment assignment. The primary outcome was the duration of symptoms rated moderately bad or worse (measured using a validated diary) for up to 28 days or until symptoms resolved. The primary outcome and safety were assessed in the intention-to-treat population. The trial is registered with the ISRCTN Registry (ISRCTN79914298). FINDINGS: Between Nov 9, 2016, and March 17, 2020, 432 children (not including six who withdrew permission for use of their data after randomisation) were randomly assigned to the antibiotics group (n=221) or the placebo group (n=211). Complete data for symptom duration were available for 317 (73%) patients; missing data were imputed for the primary analysis. Median durations of moderately bad or worse symptoms were similar between the groups (5 days [IQR 4-11] in the antibiotics group vs 6 days [4-15] in the placebo group; hazard ratio [HR] 1·13 [95% CI 0·90-1·42]). No differences were seen for the primary outcome between the treatment groups in the five prespecified clinical subgroups (patients with chest signs, fever, physician rating of unwell, sputum or chest rattle, and short of breath). Estimates from complete-case analysis and a per-protocol analysis were similar to the imputed data analysis. INTERPRETATION: Amoxicillin for uncomplicated chest infections in children is unlikely to be clinically effective either overall or for key subgroups in whom antibiotics are commonly prescribed. Unless pneumonia is suspected, clinicians should provide safety-netting advice but not prescribe antibiotics for most children presenting with chest infections. FUNDING: National Institute for Health Research.

C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations.

BACKGROUND: Point-of-care testing of C-reactive protein (CRP) may be a way to reduce unnecessary use of antibiotics without harming patients who have acute exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: We performed a multicenter, open-label, randomized, controlled trial involving patients with a diagnosis of COPD in their primary care clinical record who consulted a clinician at 1 of 86 general medical practices in England and Wales for an acute exacerbation of COPD. The patients were assigned to receive usual care guided by CRP point-of-care testing (CRP-guided group) or usual care alone (usual-care group). The primary outcomes were patient-reported use of antibiotics for acute exacerbations of COPD within 4 weeks after randomization (to show superiority) and COPD-related health status at 2 weeks after randomization, as measured by the Clinical COPD Questionnaire, a 10-item scale with scores ranging from 0 (very good COPD health status) to 6 (extremely poor COPD health status) (to show noninferiority). RESULTS: A total of 653 patients underwent randomization. Fewer patients in the CRP-guided group reported antibiotic use than in the usual-care group (57.0% vs. 77.4%; adjusted odds ratio, 0.31; 95% confidence interval [CI], 0.20 to 0.47). The adjusted mean difference in the total score on the Clinical COPD Questionnaire at 2 weeks was -0.19 points (two-sided 90% CI, -0.33 to -0.05) in favor of the CRP-guided group. The antibiotic prescribing decisions made by clinicians at the initial consultation were ascertained for all but 1 patient, and antibiotic prescriptions issued over the first 4 weeks of follow-up were ascertained for 96.9% of the patients. A lower percentage of patients in the CRP-guided group than in the usual-care group received an antibiotic prescription at the initial consultation (47.7% vs. 69.7%, for a difference of 22.0 percentage points; adjusted odds ratio, 0.31; 95% CI, 0.21 to 0.45) and during the first 4 weeks of follow-up (59.1% vs. 79.7%, for a difference of 20.6 percentage points; adjusted odds ratio, 0.30; 95% CI, 0.20 to 0.46). Two patients in the usual-care group died within 4 weeks after randomization from causes considered by the investigators to be unrelated to trial participation. CONCLUSIONS: CRP-guided prescribing of antibiotics for exacerbations of COPD in primary care clinics resulted in a lower percentage of patients who reported antibiotic use and who received antibiotic prescriptions from clinicians, with no evidence of harm. (Funded by the National Institute for Health Research Health Technology Assessment Program; PACE Current Controlled Trials number, ISRCTN24346473.).

International comparison of guidelines for management of impetigo: a systematic review.

BACKGROUND: Impetigo is a common superficial skin infection that affects people worldwide and is usually treated with antibiotics; therefore, its management has implications for global antibiotic stewardship. OBJECTIVE: This systematic review and narrative synthesis compares and contrasts international impetigo management guidelines. METHODS: Guidelines for treatment of impetigo that were produced by a national authority; available to primary care physicians; and published since 2008 were included. Following a comprehensive search strategy, data extraction from eligible studies was performed independently in duplicate. Details of antiseptic and antibiotic treatment; methicillin-resistant Staphylococcus aureus treatment; and conservative management and preventative measures were tabulated and analysed descriptively. RESULTS: Fifty-one guidelines were included from 42 different countries. All guidelines recommended systemic antibiotics, 78% of these only for widespread lesions or failure of topical antibiotic treatment. The first-line systemic antibiotic treatment was restricted to narrow-spectrum options in 21 (41%) whilst 7 (14%) recommended only broad-spectrum antibiotics first-line. Thirty-four (67%) guidelines included recommendations for topical antibiotic use. Twenty guidelines (39%) did not mention antiseptic treatment for impetigo. Guidelines did not always provide clear indications for different treatment options. CONCLUSIONS: Despite potentially equal efficacy to systemic antibiotics, only two-thirds of guidelines include topical antibiotic options. Many fail to include recommendations for non-antibiotic treatments such as antiseptics, preventative measures and conservative management, despite potential for antibiotic-sparing. Provision of clear definitions of disease severity and indications for treatment would enhance the ability of clinicians to adhere to recommendations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018117770.

Clinical prediction of laboratory-confirmed influenza in adults with influenza-like illness in primary care. A randomized controlled trial secondary analysis in 15 European countries.

BACKGROUND: Clinical findings do not accurately predict laboratory diagnosis of influenza. Early identification of influenza is considered useful for proper management decisions in primary care. OBJECTIVE: We evaluated the diagnostic value of the presence and the severity of symptoms for the diagnosis of laboratory-confirmed influenza infection among adults presenting with influenza-like illness (ILI) in primary care. METHODS: Secondary analysis of patients with ILI who participated in a clinical trial from 2015 to 2018 in 15 European countries. Patients rated signs and symptoms as absent, minor, moderate, or major problem. A nasopharyngeal swab was taken for microbiological identification of influenza and other microorganisms. Models were generated considering (i) the presence of individual symptoms and (ii) the severity rating of symptoms. RESULTS: A total of 2,639 patients aged 18 or older were included in the analysis. The mean age was 41.8 ± 14.7 years, and 1,099 were men (42.1%). Influenza was microbiologically confirmed in 1,337 patients (51.1%). The area under the curve (AUC) of the model for the presence of any of seven symptoms for detecting influenza was 0.66 (95% confidence interval [CI]: 0.65-0.68), whereas the AUC of the symptom severity model, which included eight variables-cough, fever, muscle aches, sweating and/or chills, moderate to severe overall disease, age, abdominal pain, and sore throat-was 0.70 (95% CI: 0.69-0.72). CONCLUSION: Clinical prediction of microbiologically confirmed influenza in adults with ILI is slightly more accurate when based on patient reported symptom severity than when based on the presence or absence of symptoms.

Influenza is usually diagnosed clinically. However, the accuracy of a diagnosis of influenza based on clinical features is limited because symptoms overlap considerably with those caused by other microorganisms. This study examined whether identification of the severity rather than the presence of key signs and symptoms could aid in the diagnosis of influenza, thereby helping clinicians to determine when antiviral agent use is appropriate. The authors used the database of a previous randomized clinical trial on the effectiveness of an antiviral carried out in primary care centers in 15 countries in Europe during three epidemic periods from 2015/2016 to 2017/2018. Participants with influenza symptoms were included and they were asked about the presence and severity of different symptoms during the baseline visit with their doctors and a nasopharyngeal swab was taken for microbiological analysis. Overall, only 51% of the patients aged 18 or older had a confirmed influenza infection. Clinical findings are not particularly useful for confirming or excluding the diagnosis of influenza. However, the results of our study recommend considering how intense the different symptoms are, since key symptoms rated as moderate or severe are slightly better for predicting flu rather than the presence or absence of these symptoms.

Biomarkers to guide the use of antibiotics for acute exacerbations of COPD (AECOPD): a systematic review and meta-analysis.

BACKGROUND: Antibiotics are frequently prescribed for acute exacerbations of COPD (AECOPD) even though most do not have a bacterial aetiology. Biomarkers may help clinicians target antibiotic use by identifying AECOPD caused by bacterial pathogens. We aimed to summarise current evidence on the diagnostic accuracy of biomarkers for detecting bacterial versus non-bacterial AECOPD. METHODS: We searched Embase and Medline using a search strategy including terms for COPD, biomarkers and bacterial infection. Data regarding diagnostic accuracy for each biomarker in predicting bacterial cause of exacerbation were extracted and summarised. We used to QUADAS-2 tool to assess risk of bias. RESULTS: Of 509 papers identified, 39 papers evaluating 61 biomarkers were eligible for inclusion. Moderate quality evidence was found for associations between serum C-reactive protein (CRP), serum procalcitonin (PCT), sputum interleukin (IL)-8 and sputum tumour necrosis factor alpha (TNF-α), and the presence of bacterial pathogens in the sputum of patients with AECOPD. Having bacterial pathogens was associated with a mean difference (higher) CRP and PCT of 29.44 mg/L and 0.76 ng/mL respectively. There was inconsistent or weak evidence for associations between bacterial AECOPD and higher levels of sputum IL-1ß, IL-6, myeloperoxidase (MPO) and neutrophil elastase (NE). We did not find any consistent evidence of diagnostic value for other biomarkers. CONCLUSIONS: There is moderate evidence from heterogeneous studies that serum CRP and PCT are of value in differentiating bacterial from non-bacterial AECOPD, and little evidence for other biomarkers. Further high-quality research on the role of biomarkers in identifying bacterial exacerbations is needed.

Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial.

BACKGROUND: Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups. METHODS: We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921. FINDINGS: Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group. INTERPRETATION: Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner. FUNDING: European Commission's Seventh Framework Programme.

Identifying factors associated with spontaneous restoration of hearing in children with otitis media with effusion.

OBJECTIVES: To identify predictors of acceptable hearing at 5 weeks, 6 and 12 months in children with bilateral otitis media with effusion (OME). DESIGN AND SETTING: Secondary analysis of OSTRICH data, conducted in hospital ear, nose and throat (ENT) and paediatric audiology and audiovestibular medicine departments across Wales and England. PARTICIPANTS: The OSTRICH study included 389 children aged 2-8 years with bilateral hearing loss attributable toOME for at least 3 months. MAIN OUTCOME MEASURES: Baseline, 5-week, 6- and 12-month audiology measurements were collected and logistic regression models used to identify pre-randomisation baseline variables that predicted return of acceptable hearing, which was defined as less than or equal to 20 dB hearing loss averaged within the frequencies of 0.5, 1, 2 and 4 kHz in at least one ear in children assessed by pure tone audiometry, ear-specific insert visual reinforcement audiometry or ear-specific play audiometry less than or equal to 25 dB hearing loss averaged within the frequencies of 0.5, 1, 2 and 4 kHz in children assessed by sound-field visual reinforcement audiometry or sound-field performance/play audiometry, based on national guidelines. RESULTS: Less severe baseline hearing loss across both ears most consistently predicted acceptable hearing at 5 weeks (adjusted odds ratio [aOR] 0.91, 95% CI 0.87-0.95), 6 months (0.94 [0.90-0.98]) and 12 months (0.93 [0.89-0.97]). Negative history of atopy (2.05 [1.16-3.61]), never using hearing aids (aOR 2.16 [1.04-4.48]), and being male (1.75 [1.02-2.99]) were significant at 6 months, but not at 12 months. Symptom duration was a predictor at 5 weeks, but not at 6 or 12 months. CONCLUSIONS: Milder baseline hearing loss most consistently predicts acceptable hearing at 5 weeks, 6 and 12 months in children with chronic OME. Negative history of atopy, never using hearing aids, and male gender are associated with better prognosis. These predictors can be used to identify children that may not require treatment.

Antibiotic use and deprivation: an analysis of Welsh primary care antibiotic prescribing data by socioeconomic status.

OBJECTIVES: To examine the association between socioeconomic status (SES) and antibiotic prescribing, controlling for the presence of common chronic conditions and other potential confounders and variation amongst GP practices and clusters. METHODS: This was an electronic cohort study using linked GP and Welsh Index of Multiple Deprivation (WIMD) data. The setting was GP practices contributing to the Secure Anonymised Information Linkage (SAIL) Databank 2013-17. The study involved 2.9 million patients nested within 339 GP practices, nested within 67 GP clusters. RESULTS: Approximately 9 million oral antibiotics were prescribed between 2013 and 2017. Antibiotic prescribing rates were associated with WIMD quintile, with more deprived populations receiving more antibiotics. This association persisted after controlling for patient demographics, smoking, chronic conditions and clustering by GP practice and cluster, with those in the most deprived quintile receiving 18% more antibiotic prescriptions than those in the least deprived quintile (incidence rate ratio = 1.18; 95% CI = 1.181-1.187). We found substantial unexplained variation in antibiotic prescribing rates between GP practices [intra-cluster correlation (ICC) = 47.31%] and GP clusters (ICC = 12.88%) in the null model, which reduced to ICCs of 3.50% and 0.85% for GP practices and GP clusters, respectively, in the final adjusted model. CONCLUSIONS: Antibiotic prescribing in primary care is increased in areas of greater SES deprivation and this is not explained by differences in the presence of common chronic conditions or smoking status. Substantial unexplained variation in prescribing supports the need for ongoing antimicrobial stewardship initiatives.

Effect of Probiotic Use on Antibiotic Administration Among Care Home Residents: A Randomized Clinical Trial.

Importance: Probiotics are frequently used by residents in care homes (residential homes or nursing homes that provide residents with 24-hour support for personal care or nursing care), although the evidence on whether probiotics prevent infections and reduce antibiotic use in these settings is limited. Objective: To determine whether a daily oral probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12 compared with placebo reduces antibiotic administration in care home residents. Design, Setting, and Participants: Placebo-controlled randomized clinical trial of 310 care home residents, aged 65 years and older, recruited from 23 care homes in the United Kingdom between December 2016 and May 2018, with last follow-up on October 31, 2018. Interventions: Study participants were randomized to receive a daily capsule containing a probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12 (total cell count per capsule, 1.3 × 1010 to 1.6 × 1010) (n = 155), or daily matched placebo (n = 155), for up to 1 year. Main Outcomes and Measures: The primary outcome was cumulative antibiotic administration days for all-cause infections measured from randomization for up to 1 year. Results: Among 310 randomized care home residents (mean age, 85.3 years; 66.8% women), 195 (62.9%) remained alive and completed the trial. Participant diary data (daily data including study product use, antibiotic administration, and signs of infection) were available for 98.7% randomized to the probiotic group and 97.4% randomized to placebo. Care home residents randomized to the probiotic group had a mean of 12.9 cumulative systemic antibiotic administration days (95% CI, 0 to 18.05), and residents randomized to placebo had a mean of 12.0 days (95% CI, 0 to 16.95) (absolute difference, 0.9 days [95% CI, -3.25 to 5.05]; adjusted incidence rate ratio, 1.13 [95% CI, 0.79 to 1.63]; P = .50). A total of 120 care home residents experienced 283 adverse events (150 adverse events in the probiotic group and 133 in the placebo group). Hospitalizations accounted for 94 of the events in probiotic group and 78 events in the placebo group, and deaths accounted for 33 of the events in the probiotic group and 32 of the events in the placebo group. Conclusions and Relevance: Among care home residents in the United Kingdom, a daily dose of a probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12 did not significantly reduce antibiotic administration for all-cause infections. These findings do not support the use of probiotics in this setting. Trial Registration: ISRCTN Identifier:16392920.

The effect of ventilation tube insertion on quality of life in children with persistent otitis media with effusion.

OBJECTIVES: To determine the effect of ventilation tube (VT) surgery on quality of life (QoL) in children with persistent otitis media with effusion (OME). DESIGN: Secondary analysis of trial data (oral steroids versus placebo for persistent OME), comparing QoL by history of VT surgery performed between 5 weeks and 12 months post-randomisation. Multilevel regression models were used to identify the association between VT surgery and QoL scores at 12 months, controlling for pre-exposure risk factors associated with surgery, including pre-surgery hearing level. SETTING: Ear, nose and throat (ENT), paediatric audiology and audiovestibular medicine (AVM) departments in Wales and England. PARTICIPANTS: A total of 327 children aged 2-8 years with OME symptoms for at least three months and audiometry-proven bilateral hearing loss with VT surgery status. MAIN OUTCOME MEASURES: Otitis Media questionnaire (OM8-30) and Paediatric Quality of Life Inventory (PedsQL) total and subscale scores, and the Health Utilities Index Mark 3 (HUI3) at 12 months post-randomisation. RESULTS: Participants who had VT surgery had no significant difference in OM8-30, PedsQL or HUI total scores. OM8-30 hearing difficulty (HD) subscale scores at 12 months were better in those who had VT surgery (adjusted mean difference (aMD) = -0.46 (95% confidence interval: -0.69 to -0.23), P < .001), and this varied by when the surgery occurred (aMD for surgery between 5 weeks and 6 months = -0.4 [-0.67 to -0.13], P = .004 and between 6 and 12 months = -0.54, [-0.87 to -0.22], P = .001). CONCLUSION: Ventilation tube surgery was associated with an improvement in HD-related functional health status but no change in overall QoL.

Mild-to-moderate renal pelvis dilatation identified during pregnancy and hospital admissions in childhood: An electronic birth cohort study in Wales, UK.

BACKGROUND: Chronic kidney disease (CKD) is a growing contributor to the global burden of noncommunicable diseases. Early diagnosis and treatment can reduce the severity of kidney damage and the need for dialysis or transplantation. It is not known whether mild-to-moderate renal pelvis dilatation (RPD) identified at 18-20 weeks gestation is an early indicator of renal pathology. The aim of this follow-up to the Welsh Study of Mothers and Babies was to assess the risk of hospital admission in children with mild-to-moderate antenatal RPD compared with children without this finding. We also examined how the natural history of the RPD (whether the dilatation persists in later pregnancy or postpartum) or its characteristics (unilateral versus bilateral) changed the risk of hospital admission. METHODS/FINDINGS: This population-based cohort study included singleton babies born in Wales between January 1, 2009, and December 31, 2011 (n = 22,045). We linked ultrasound scan data to routinely available data on hospital admissions from the Patient Episode Database for Wales (PEDW). The outcome was a hospital admission for urinary tract causes (defined by an expert study steering group) in the first three years of life. We used Cox regression to model time to first hospital admission, according to whether there was evidence of RPD at the fetal anomaly scan (FAS) and/or evidence of dilatation in later investigations, adjusting for other predictors of admission. We used multiple imputation with chained equations to impute values for missing data. We included 21,239 children in the analysis. The risk of at least one hospital admission was seven times greater in those with RPD (n = 138) compared with those without (n = 21,101, conditional hazard ratio [cHR] 7.23, 95% confidence interval [CI] 4.31-12.15, p < 0.001). The risk of hospital admission was higher in children with RPD at the FAS and later dilatation (cHR 25.13, 95% CI 13.26-47.64, p < 0.001) and in children without RPD at the FAS who had later dilatation (cHR 62.06, 95% CI 41.10-93.71, p < 0.001) than in children without RPD (n = 21,057). Among children with RPD at the FAS but no dilatation in later pregnancy or postpartum, we did not find an association with hospital admissions (cHR 2.16, 95% CI 0.69-6.75, p = 0.185), except when the initial dilatation was bilateral (cHR 4.77, 95% CI 1.17-19.47, p = 0.029). Limitations of the study include small numbers in subgroups (meaning that these results should be interpreted with caution), that less severe outcomes (such as urinary tract infections [UTIs] managed in the community or in outpatients) could not be included in our analysis, and that obtaining records of radiological investigations later in pregnancy and postpartum was challenging. Our conclusions were consistent after conducting sensitivity analyses to account for some of these limitations. CONCLUSIONS: In this large population-based study, children with RPD at the FAS had higher rates of hospital admissions when there was persistent dilatation in later pregnancy or postpartum. Our results can be used to improve counselling of parents and develop care pathways for antenatal screening programmes, including protocols for reporting and further investigation of RPD.

Oral steroids for resolution of otitis media with effusion in children (OSTRICH): a double-blinded, placebo-controlled randomised trial.

BACKGROUND: Children with persistent hearing loss due to otitis media with effusion are commonly managed by surgical intervention. A safe, cheap, and effective medical treatment would enhance treatment options. Underpowered, poor-quality trials have found short-term benefit from oral steroids. We aimed to investigate whether a short course of oral steroids would achieve acceptable hearing in children with persistent otitis media with effusion and hearing loss. METHODS: In this individually randomised, parallel, double-blinded, placebo-controlled trial we recruited children aged 2-8 years with symptoms attributable to otitis media with effusion for at least 3 months and with confirmed bilateral hearing loss. Participants were recruited from 20 ear, nose, and throat (ENT), paediatric audiology, and audiovestibular medicine outpatient departments in England and Wales. Participants were randomly allocated (1:1) to sequentially numbered identical prednisolone (oral steroid) or placebo packs by use of computer-generated random permuted block sizes stratified by site and child's age. The primary outcome was audiometry-confirmed acceptable hearing at 5 weeks. All analyses were by intention to treat. This trial is registered with the ISRCTN Registry, number ISRCTN49798431. FINDINGS: Between March 20, 2014, and April 5, 2016, 1018 children were screened, of whom 389 were randomised. 200 were assigned to receive oral steroids and 189 to receive placebo. Hearing at 5 weeks was assessed in 183 children in the oral steroid group and in 180 in the placebo group. Acceptable hearing was observed in 73 (40%) children in the oral steroid group and in 59 (33%) in the placebo group (absolute difference 7% [95% CI -3 to 17], number needed to treat 14; adjusted odds ratio 1·36 [95% CI 0·88-2·11]; p=0·16). There was no evidence of any significant differences in adverse events or quality-of-life measures between the groups. INTERPRETATION: Otitis media with effusion in children with documented hearing loss and attributable symptoms for at least 3 months has a high rate of spontaneous resolution. A short course of oral prednisolone is not an effective treatment for most children aged 2-8 years with persistent otitis media with effusion, but is well tolerated. One in 14 children might achieve improved hearing but not quality of life. Discussions about watchful waiting and other interventions will be supported by this evidence. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Antibiotic Prescribing for Acute Respiratory Tract Infections 12 Months After Communication and CRP Training: A Randomized Trial.

PURPOSE: C-reactive-protein (CRP) is useful for diagnosis of lower respiratory tract infections (RTIs). A large international trial documented that Internet-based training in CRP point-of-care testing, in enhanced communication skills, or both reduced antibiotic prescribing at 3 months, with risk ratios (RRs) of 0.68, 0.53, 0.38, respectively. We report the longer-term impact in this trial. METHODS: A total of 246 general practices in 6 countries were cluster-randomized to usual care, Internet-based training on CRP point-of-care testing, Internet-based training on enhanced communication skills and interactive booklet, or both interventions combined. The main outcome was antibiotic prescribing for RTIs after 12 months. RESULTS: Of 228 practices providing 3-month data, 74% provided 12-month data, with no demonstrable attrition bias. Between 3 months and 12 months, prescribing for RTIs decreased with usual care (from 58% to 51%), but increased with CRP training (from 35% to 43%) and with both interventions combined (from 32% to 45%); at 12 months, the adjusted RRs compared with usual care were 0.75 (95% CI, 0.51-1.00) and 0.70 (95% CI, 0.49-0.93), respectively. Between 3 months and 12 months, the reduction in prescribing with communication training was maintained (41% and 40%, with an RR at 12 months of 0.70 [95% CI, 0.49-0.94]). Although materials were provided for free, clinicians seldom used booklets and rarely used CRP point-of-care testing. Communication training, but not CRP training, remained efficacious for reducing prescribing for lower RTIs (RR = 0.7195% CI, 0.45-0.99, and RR = 0.76; 95% CI, 0.47-1.06, respectively), whereas both remained efficacious for reducing prescribing for upper RTIs (RR = 0.60; 95% CI, 0.37-0.94, and RR = 0.58; 95% CI, 0.36-0.92, respectively). CONCLUSIONS: Internet-based training in enhanced communication skills remains effective in the longer term for reducing antibiotic prescribing. The early improvement seen with CRP training wanes, and this training becomes ineffective for lower RTIs, the only current indication for using CRP testing.