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Background The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. Methods PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (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

Background: The safety, effectiveness and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, in patients in the community who are multiply-vaccinated and at increased risk of morbidity and mortality from COVID-19, has not been established. We aimed to determine whether molnupiravir added to usual care reduced hospital admissions/deaths among people at higher risk from COVID-19, and here report our preliminary analyses. Methods: Participants in this UK multicentre, open-label, adaptive, multi-arm, platform, randomised controlled trial were aged ≥50, or ≥18 years with comorbidities, and unwell ≤5 days with confirmed COVID-19 in the community, and were randomised to usual care or usual care plus molnupiravir (800mg twice daily for 5 days). The primary outcome measure was all-cause hospitalisation/death within 28 days, analysed using Bayesian models. The main secondary outcome measure was time to first self-reported recovery. A sub-set of participants in each group were assessed for the virology primary outcome measure of day seven SARS-CoV-2 viral load. Trial registration: ISRCTN30448031 Findings: Between December 8, 2021 and April 27, 2022, 25783 participants were randomised to molnupiravir plus usual care (n=12821) or usual care alone (n=12962). Mean (range) age of participants was 56·6 years (18 to 99), 58·6% were female, and 99% had at least one dose of a SARS-CoV-2 vaccine. The median duration of symptoms prior to randomisation was two days (IQR 1 – 3), the median number of days from symptom onset to starting to take the medication was three days (IQR 3 – 4), 87% (11109/11997) received their medication within five days of symptom onset, and 95·4% (n=11857) of participants randomised to molnupiravir reported taking molnupiravir for five days. Primary outcome measure data were available in 25000 (97%) participants and included in this analysis. 103/12516 (0·8%) hospitalisations/deaths occurred in the molnupiravir group versus 96/12484 (0·8%) in usual care alone with a posterior probability of superiority of 0·34 (adjusted odds ratio 1·061 (95% Bayesian credible interval [BCI]) 0·80 to 1·40). Estimates were similar for all subgroups. The observed median (IQR) time-to-first-recovery from randomisation was 9 (5–23) days in molnupiravir and 15 (7–not reached) days in usual care. There was an estimated benefit of 4·2 (95% BCI: 3·8 – 4·6) days in time-to-first-recovery (TTR) giving a posterior probability of superiority of >0·999 (estimated median TTR 10·3 [10·2 – 10·6] days vs 14·5 [14·2 – 14·9] days respectively; hazard ratio [95% BCI], 1·36 [1·3–1·4] days), which met the pre-specified superiority threshold. On day 7, SARS-CoV-2 virus was below detection levels in 7/34 (21%) of the molnupiravir group, versus 1/39 (3%) in the usual care group (p=0.039), and mean viral load was lower in the molnupiravir group compared with those receiving usual care [(SD) of log10(viral load) 3·82 (1·40) in the molnupiravir group and 4.93 (1·38) in the usual care group, (P Interpretation: In this preliminary analysis, we found that molnupiravir did not reduce already low hospitalisations/deaths among higher risk, vaccinated adults with COVID-19 in the community, but resulted in faster time to recovery, and reduced viral detection and load. Funding: This project is funded by the NIHR (NIHR135366). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Background Chronic cough due to chronic bronchitis (CB) causes significant impairment in quality of life, and effective treatment strategies are needed. We conducted a systematic review on the management of chronic cough due to CB to update the recommendations and suggestions of the American College of Chest Physicians (CHEST) 2006 guideline on this topic. Methods This systematic review asked three questions: (1) What are the clinical features of the history that suggest a patient's cough-phlegm syndrome is due to CB? (2) Can treatment of stable CB improve or eliminate chronic cough? (3) Can therapy that targets chronic cough due to CB prevent or reduce the occurrence of acute CB exacerbations? Studies of adult patients with CB were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using the CHEST organization methodology. Results The search strategy used an assortment of descriptors and assessments to identify studies of chronic cough due to CB. Conclusions The evidence supporting the management of chronic cough due to CB is limited overall and of low quality. This article provides guidance on treatment by presenting suggestions based on the best currently available evidence and identifies gaps in our knowledge and areas for future research.

Background Asthma and non-asthmatic eosinophilic bronchitis (NAEB) are among the commonest causes of chronic cough in adults. We sought to determine the role of non-invasive measurements of airway inflammation, including induced sputum and fractional exhaled nitric oxide, in the evaluation of cough associated with asthma, and what the best treatment is for cough due to asthma or NAEB. Methods We undertook three systematic reviews of randomized controlled trials and observational trials of adults and adolescents > 12 years of age with a chronic cough due to asthma or NAEB. Eligible studies were identified in MEDLINE, CENTRAL, and SCOPUS and assessed for relevance and quality. Guidelines were developed and voted upon using CHEST guideline methodology. Results Of the citations reviewed, 3/1,175, 53/656, and 6/134 were identified as being eligible for inclusion in the three systematic reviews, respectively. In contrast to established guidelines for asthma therapies in general and the inclusion in some guidelines for a role of biomarkers of airway inflammation to guide treatment in severe disease, the evidence of specific benefit related to the use of non-invasive biomarkers in patients with chronic cough due to asthma was weak. The best therapeutic option for cough in asthma or NAEB is inhaled corticosteroids followed by leukotriene receptor antagonism. Conclusions This guideline offers recommendations on the role of non-invasive measurements of airway inflammation and treatment for cough due to asthma or NAEB based on the available literature, and identifies gaps in knowledge and areas for future research.

Background Cough is one of the most common presenting symptoms to general practitioners. The objective of this article is to collate the pediatric components of the CHEST chronic cough guidelines that have recently updated the 2006 guidelines to assist general and specialist medical practitioners in the evaluation and management of children who present with chronic cough. Methods We reviewed all current CHEST Expert Cough Panel's statements and extracted recommendations and suggestions relating to children aged ≤ 14 years with chronic cough (> 4 weeks duration). Additionally, we undertook systematic reviews to update other sections we considered relevant and important. Results The eight recent CHEST guidelines relevant to children, based on systematic reviews, reported some high-quality evidence in the management of chronic cough in children (eg, use of algorithms and management of wet/productive cough using appropriate antibiotics). However, much evidence is still inadequate, particularly in the management of non-specific cough in the community. Conclusions The recommendations and suggestions related to the management of chronic cough in the pediatric age group have been based upon high-quality systematic reviews and are summarized in this article. Compared to the 2006 Cough Guidelines, there is now high-quality evidence for some aspects of the management of chronic cough in children. However, further studies particularly in primary health care are required.

Background Evidence for the diagnosis and management of cough due to acute bronchitis in immunocompetent adult outpatients was reviewed as an update to the 2006 "Chronic Cough Due to Acute Bronchitis: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines." Methods Acute bronchitis was defined as an acute lower respiratory tract infection manifested predominantly by cough with or without sputum production, lasting no more than 3 weeks with no clinical or any recent radiographic evidence to suggest an alternative explanation. Two clinical population, intervention, comparison, outcome questions were addressed by systematic review in July 2017: (1) the role of investigations beyond the clinical assessment of patients presenting with suspected acute bronchitis, and (2) the efficacy and safety of prescribing medication for cough in acute bronchitis. An updated search was undertaken in May 2018. Results No eligible studies relevant to the first question were identified. For the second question, only one relevant study met eligibility criteria. This study found no difference in number of days with cough between patients treated with an antibiotic or an oral nonsteroidal antiinflammatory agent compared with placebo. Clinical suggestions and research recommendations were made based on the consensus opinion of the CHEST Expert Cough Panel. Conclusions The panelists suggested that no routine investigations be ordered and no routine medications be prescribed in immunocompetent adult outpatients first presenting with cough due to suspected acute bronchitis, until such investigations and treatments have been shown to be safe and effective at making cough less severe or resolve sooner. If the cough due to suspected acute bronchitis persists or worsens, a reassessment and consideration of targeted investigations should be considered.

Aims: To rank the effectiveness of medicinal plants for glycaemic control in Type 2 Diabetes (T2DM).Methods: MEDLINE, EMBASE, CINAHL and Cochrane Central were searched in October 2020. We included meta-analyses of randomised controlled clinical trials measuring the effectiveness of medicinal plants on HbA1c and/or Fasting Plasma Glucose (FPG) in patients with T2DM.Results: Twenty five meta-analyses reported the effects of 18 plant-based remedies. Aloe vera leaf gel, Psyllium fibre and Fenugreek seeds had the largest effects on HbA1c: mean difference –0.99% [95% CI−1.75, −0.23], −0.97% [95% CI −1.94, −0.01] and −0.85% [95% CI −1.49, −0.22] respectively. Four other remedies reduced HbA1c by at least 0.5%: Nigellasativa, Astragalus membranaceus, and the traditional Chinese formulae Jinqi Jiangtang and Gegen Qinlian. No serious adverse effects were reported. Several other herbal medicines significantly reduced FPG. Tea and tea extracts (Camellia sinensis) were ineffective. However, in some trials duration of follow-up was insufficient to measure the full effect on HbA1c (Conclusion: Several medicinal plants appear to be as effective as conventional antidiabetic treatments for reducing HbA1c. Rigorous trials with at least 3 months’ follow-up are needed to ascertain the effects of promising plant-based preparations on diabetes.

BackgroundRespiratory tract infections (RTIs) account for 60% of antibiotic prescribing in primary care. Several clinical prediction rules (CPRs) have been developed to help reduce unnecessary prescribing for RTIs, but there is a lack of studies exploring whether or how these CPRs are being used in UK general practice.AimTo explore UK GPs’ views and experiences with regards to RTI CPRs, and to identify barriers and facilitators to their use in practice.Design & settingA qualitative analysis of interviews with in-hours GPs working in the South and South West of England.MethodSemi-structured qualitative telephone interviews were conducted, digitally recorded, transcribed verbatim, and analysed using an inductive thematic approach. Patient and public involvement representatives contributed to study design and interpretation of findings.ResultsThirty-two GPs were interviewed. Some CPRs were more commonly used than others. Participants used CPRs to facilitate patient—clinician discussion, confirm and support their decision, and document the consultation. GPs also highlighted concerns including lack of time, inability of CPRs to incorporate patient complexity, a shift in focus from the patient during consultations, and limited use in remote consultation (during the COVID-19 pandemic).ConclusionThis study highlights the need for user-friendly CPRs that are readily integrated into computer systems, and easily embedded into routine practice to complement clinical decision-making. Existing CPRs need to be validated for other populations where demographics and clinical characteristics may differ, as well different settings including remote consultations and self-assessment.

INTRODUCTION: Atrial fibrillation (AF) is a common arrhythmia associated with 30% of strokes, as well as other cardiovascular disease, dementia and death. AF meets many criteria for screening, but there is limited evidence that AF screening reduces stroke. Consequently, no countries recommend national screening programmes for AF. The Screening for Atrial Fibrillation with ECG to Reduce stroke (SAFER) trial aims to determine whether screening for AF is effective at reducing risk of stroke. The aim of the pilot study is to assess feasibility of the main trial and inform implementation of screening and trial procedures. METHODS AND ANALYSIS: SAFER is planned to be a pragmatic randomised controlled trial (RCT) of over 100 000 participants aged 70 years and over, not on long-term anticoagulation therapy at baseline, with an average follow-up of 5 years. Participants are asked to record four traces every day for 3 weeks on a hand-held single-lead ECG device. Cardiologists remotely confirm episodes of AF identified by the device algorithm, and general practitioners follow-up with anticoagulation as appropriate. The pilot study is a cluster RCT in 36 UK general practices, randomised 2:1 control to intervention, recruiting approximately 12 600 participants. Pilot study outcomes include AF detection rate, anticoagulation uptake and other parameters to incorporate into sample size calculations for the main trial. Questionnaires sent to a sample of participants will assess impact of screening on psychological health. Process evaluation and qualitative studies will underpin implementation of screening during the main trial. An economic evaluation using the pilot data will confirm whether it is plausible that screening might be cost-effective. ETHICS AND DISSEMINATION: The London-Central Research Ethics Committee (19/LO/1597) and Confidentiality Advisory Group (19/CAG/0226) provided ethical approval. Dissemination will be via publications, patient-friendly summaries, reports and engagement with the UK National Screening Committee. TRIAL REGISTRATION NUMBER: ISRCTN72104369., The SAFER pilot study and main trial are funded by the National Institute for Health and Care Research (NIHR) [Programme Grants for Applied Research Programme (Reference Number RP-PG-0217-20007)]. The SAFER feasibility study is funded by the NIHR [School for Primary Care Research (SPCR-2014-10043, project 410)]. SAFER is a contributor to / partner of AFFECT-EU receiving funding from the European Union’s Horizon 2020 research and innovation Programme under grant agreement NO. 847770. RM and JL are supported by the Wellcome Trust as part of the Wellcome Trust PhD Programme for Primary Care Clinicians [grant number 203921/Z/16/Z]. JB, SH and AP are based in The Healthcare Improvement Studies Institute (THIS Institute), University of Cambridge. THIS Institute is supported by the Health Foundation, an independent charity committed to bringing about better health and healthcare for people in the UK. JB is supported by the Health Foundation’s grant to the University of Cambridge for The Healthcare Improvement Studies (THIS) Institute (RG88620). JM and FDRH are NIHR Senior Investigators. FDRH acknowledges support from NIHR ARC OTV and Oxford BRC (OUT). RJM is an NIHR Senior Investigator and acknowledges support from NIHR ARC OTV. NA is supported by a Health Foundation Improvement Science Fellowship and also by the NIHR Applied Research Collaboration East Midlands (ARC EM). RJ is an NIHR-funded Academic Clinical Lecturer. The University of Cambridge has received salary support in respect of SJG from the NHS in the East of England through the Clinical Academic Reserve. BF reports grants to the Heart Research Institute. All the funders and sponsors had no involvement in the development of this protocol and will have no involvement in any aspect of the study itself. The views expressed are those of the author(s) and not necessarily those of the NHS, the Wellcome Trust, the NIHR or the UK Department of Health and Social Care.

BackgroundOptimal management of hypertension in older patients with multimorbidity is a cornerstone of primary care practice. Despite emphasis on personalised approaches to treatment in older patients, there is little guidance on how to achieve medication reduction when GPs are concerned that possible risks outweigh potential benefits of treatment. Mindlines — tacit, internalised guidelines developed over time from multiple sources — may be of particular importance in such situations.AimTo explore GPs’ decision-making on deprescribing antihypertensives in patients with multimorbidity aged ≥80 years, drawing on the concept of mindlines.Design and settingQualitative interview study set in English general practice.MethodThematic analysis of face-to-face interviews with a sample of 15 GPs from seven practices in the East of England, using a chart-stimulated recall approach to explore approaches to treatment for older patients with multimorbidity with hypertension.ResultsGPs are typically confident making decisions to deprescribe antihypertensive medication in older patients with multimorbidity when prompted by a trigger, such as a fall or adverse drug event. GPs are less confident to attempt deprescribing in response to generalised concerns about polypharmacy, and work hard to make sense of multiple sources (including available evidence, shared experiential knowledge, and non-clinical factors) to guide decision-making.ConclusionIn the absence of a clear evidence base on when and how to attempt medication reduction in response to concerns about polypharmacy, GPs develop ‘mindlines’ over time through practicebased experience. These tacit approaches to making complex decisions are critical to developing confidence to attempt deprescribing and may be strengthened through reflective practice.

BackgroundAntibiotic overuse is linked to increased risk of antimicrobial resistance. Long-term antibiotics are commonly used for treating acne and prophylaxis of urinary tract infection. Their contribution to the overall burden of antibiotic use is relatively unknown.AimTo describe the volume of commonly prescribed long-term (≥28 days) antibiotic prescriptions in adolescents and young adults, trends over time, and comparisons with acute prescriptions.Design and settingA retrospective cohort study using UK electronic primary care records.MethodPatients born between 1979 and 1996 and with data in the Care and Health Information Analytics database were included. The main outcome measures were antibiotic prescription rates per 1000 person-years and antibiotic prescription days per person-year between the ages of 11 and 21.ResultsIn total, 320 722 participants received 710 803 antibiotic prescriptions between the ages of 11 and 21 years from 1998 to 2017. Of these 710 803 prescriptions, 191 443 (26.93%) were for long-term antibiotics (≥28 days and ≤6 months in duration). Long-term antibiotics accounted for more than two-thirds (72.48%) of total antibiotic exposure (days per person-year). Total long-term antibiotic prescribing peaked in 2013 at just under 6 days per person-year and declined to around 4 days in 2017.ConclusionAmong adolescents and young adults, exposure to long-term antibiotics (primarily lymecycline used for acne) was much greater than for acute antibiotics and is likely to make an important contribution to antimicrobial resistance. Urgent action is needed to reduce unnecessary exposure to long-term antibiotics in this group. Increasing the use of, and adherence to, effective non-antibiotic treatments for acne is key to achieving this.

Background Care homes are an increasingly important sector of care. Care home residents are particularly vulnerable to infections and are often prescribed antibiotics, driving antibiotic resistance. Probiotics may be a cheap and safe way to reduce antibiotic use. Efficacy and possible mechanisms of action are yet to be rigorously evaluated in this group. Objective The objective was to evaluate efficacy and explore mechanisms of action of a daily oral probiotic combination in reducing antibiotic use and infections in care home residents. Design This was a multicentre, parallel, individually randomised, placebo-controlled, double-blind trial, with qualitative evaluation and mechanistic studies. Setting A total of 310 care home residents were randomised from 23 UK care homes (from December 2016 to May 2018). Participants The participants were care home residents aged ≥ 65 years who were willing and able to give informed consent or, if they lacked capacity to consent, had a consultee to advise about participation on their behalf. Intervention A daily capsule containing an oral probiotic combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12 (n = 155) or matched placebo (n = 155) for up to 1 year. Main outcome measures The primary outcome was cumulative systemic antibiotic administration days for all-cause infections. Secondary outcomes included incidence and duration of infections, antibiotic-associated diarrhoea, quality of life, hospitalisations and the detection of resistant Enterobacterales cultured from stool samples (not exclusively). Methods Participants were randomised (1 : 1) to receive capsules containing probiotic or matched placebo. Minimisation was implemented for recruiting care home and care home resident sex. Care home residents were followed up for 12 months with a review by a research nurse at 3 months and at 6–12 months post randomisation. Care home residents, consultees, care home staff and all members of the trial team, including assessors and statisticians, were blinded to group allocation. Results Care home residents who were randomised to probiotic had a mean 12.9 cumulative systemic antibiotic administration days (standard error 1.49 days) (n = 152) and care home residents randomised to placebo had a mean 12.0 cumulative systemic antibiotic administration days (standard error 1.50 days) (n = 153) (adjusted incidence rate ratio = 1.13, 95% confidence interval 0.79 to 1.63; p = 0.495). There was no evidence of any beneficial effects on incidence and duration of infections, antibiotic-associated diarrhoea, quality of life, hospitalisations, the detection of resistant Enterobacterales cultured from stool samples or other secondary outcomes. There was no evidence that this probiotic combination improved blood immune cell numbers, subtypes or responses to seasonal influenza vaccination. Conclusions Care home residents did not benefit from daily consumption of a combination of the probiotics Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12 to reduce antibiotic consumption. Limitations Limitations included the following: truncated follow-up of some participants; higher than expected probiotics in stool samples at baseline; fewer events than expected meant that study power may have been lower than anticipated; standard infection-related definitions were not used; and findings are not necessarily generalisable because effects may be strain specific and could vary according to patient population. Future work Future work could involve further rigorous efficacy, mechanisms and effectiveness trials of other probiotics in other population groups and settings regarding antibiotic use and susceptibility to and recovery from infections, in which potential harms should be carefully studied. Trial registration Current Controlled Trials ISRCTN16392920. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 7. See the NIHR Journals Library website for further project information.

BackgroundSore throat resulting from pharyngotonsillitis is one of the commonest reasons for primary care consultation and inappropriate antibiotic prescription and finding effective alternative treatments is important.ObjectivesTo review the evidence for using the probiotic Streptococcus salivarius K12 (SsK12) for the prevention or treatment of pharyngotonsillitis.Data SourcesPubMed, Embase, CINAHL and Cochrane Library.Study eligibility criteriaRandomized controlled trials (RCTs).ParticipantsAdults or children.InterventionsSsK12 as active treatment or prophylaxis, against pharyngotonsillitis.MethodsLiterature search.ResultsFour articles were identified (1846 participants). All were deemed to be of poor quality using the Cochrane risk-of-bias assessment. Two trials studied SsK12 prophylaxis for streptococcal pharyngitis (children without history of recurrence). One compared daily administration of SsK12 to no treatment over 6 months (n = 222, age 33–45 months), reporting significantly lower incidence in the SsK12 group (16.2% vs. 48.6%, p n = 1314, 5–14 years) found no significant difference (7.8% vs. 8.8%, p 0.34) with SsK12 (administered on school days). Another trial found daily SsK12 to significantly protect children (n = 250, 6–7 years) against chronic adenoiditis exacerbation over 3 months compared to no treatment (71.7% vs. 100%, p SsK12 for acute pharyngotonsillitis (concurrently with penicillin) showed no significant benefit. In all trials, SsK12 was safe and well tolerated.ConclusionsSsK12 appears safe and well tolerated. However, further RCTs are required to establish its role as a prophylactic therapy, particularly among patients experiencing frequent exacerbations of pharyngitis. In the acute setting, SsK12 is unlikely to be effective if given concurrently with antibiotics; however, further RCTs should establish its role as an alternative to antibiotics in nonsevere cases or when prescribed after antibiotic therapy for the prevention of disease recurrence and/or secondary infection.

Background The decision to treat a suspected case of pertussis with antibiotics is usually based on a clinical diagnosis rather than waiting for laboratory confirmation. The current guideline focuses on making the clinical diagnosis of pertussis-associated cough in adults and children. Methods The American College of Chest Physicians (CHEST) methodologic guidelines and the Grading of Recommendations, Assessment, Development, and Evaluation framework were used. The Expert Cough Panel based their recommendations on findings from a systematic review that was recently published on the topic; final grading was reached by consensus according to Delphi methodology. The systematic review was carried out to answer the Key Clinical Question: In patients presenting with cough, how can we most accurately diagnose from clinical features alone those who have pertussis-associated cough as opposed to other causes of cough? Results In adults, after pre-specified meta-analysis exclusions, pooled estimates of sensitivity and specificity were generated for only 4 clinical features: paroxysmal cough, post-tussive vomiting, inspiratory whooping, and absence of fever. Both paroxysmal cough and absence of fever had high sensitivity (93.2% [95% CI, 83.2-97.4] and 81.8% [95% CI, 72.2-88.7], respectively) and low specificity (20.6% [95% CI, 14.7-28.1] and 18.8% [95% CI, 8.1-37.9]). Inspiratory whooping and posttussive vomiting had a low sensitivity (32.5% [95% CI, 24.5-41.6] and 29.8% [95% CI, 18.0-45.2]) but high specificity (77.7% [95% CI, 73.1-81.7] and 79.5% [95% CI, 69.4-86.9]). In children, after pre-specified meta-analysis exclusions, pooled estimates of sensitivity and specificity were generated for only 1 clinical feature in children (0-18 years): posttussive vomiting. Posttussive vomiting in children was only moderately sensitive (60.0% [95% CI, 40.3-77.0]) and specific (66.0% [95% CI, 52.5-77.3]). Conclusions In adults with acute (

Aging is associated with changes to the immune system, collectively termed immunosenescence and inflammageing. However, the relationships among age, frailty, and immune parameters in older people resident in care homes are not well described. We assessed immune and inflammatory parameters in 184 United Kingdom care home residents aged over 65 years and how they relate to age, frailty index, and length of care home residence. Linear regression was used to identify the independent contribution of age, frailty, and length of care home residence to the various immune parameters as dependent variables. Participants had a mean age (±SD) of 85.3 ± 7.5 years, had been residing in the care home for a mean (±SD) of 1.9 ± 2.2 years at the time of study commencement, and 40.7% were severely frail. Length of care home residence and frailty index were correlated but age and frailty index and age and length of care home residence were not significantly correlated. All components of the full blood count, apart from total lymphocytes, were within the reference range; 31% of participants had blood lymphocyte numbers below the lower value of the reference range. Among the components of the full blood count, platelet numbers were positively associated with frailty index. Amongst plasma inflammatory markers, C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1ra), soluble E-selectin and interferon gamma-induced protein 10 (IP-10) were positively associated with frailty. Plasma soluble vascular cell adhesion molecule 1 (sVCAM-1), IP-10 and tumor necrosis factor receptor II (TNFRII) were positively associated with age. Plasma monocyte chemoattractant protein 1 was positively associated with length of care home residence. Frailty was an independent predictor of platelet numbers, plasma CRP, IL-1ra, IP-10, and sE-selectin. Age was an independent predictor of activated monocytes and plasma IP-10, TNFRII and sVCAM-1. Length of care home residence was an independent predictor of plasma MCP-1. This study concludes that there are independent links between increased frailty and inflammation and between increased age and inflammation amongst older people resident in care homes in the United Kingdom. Since, inflammation is known to contribute to morbidity and mortality in older people, the causes and consequences of inflammation in this population should be further explored.

© 2020 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society. BACKGROUND/OBJECTIVES: Randomized controlled trials are used to inform clinical guidelines on the management of hypertension in older adults, but it is unclear to what extent these trials represent the general population attending routine clinical practice. This study aimed to define the proportion and characteristics of patients eligible for hypertension trials conducted in older people. DESIGN: Cross-sectional study. SETTING: A total of 24 general practices in England. PARTICIPANTS: Anonymized electronic health record data from all individuals aged 80 and older. MEASUREMENTS: Descriptive statistics were used to define the proportion and characteristics of patients eligible for two previous medication intensification trials (HYVET, SPRINT) and one medication reduction trial (OPTiMISE). A logistic regression model was constructed to estimate predictors of eligibility for each trial. RESULTS: Of 15,376 patients identified, 268 (1.7%; 95% confidence interval [CI] = 1.5–2.0%), 5,290 (34.4%; 95%CI = 33.7–35.2%), and 3,940 (25.6%; 95%CI = 24.9–26.3%) were eligible for the HYVET, SPRINT, and OPTiMISE trials, respectively. Between 5.6% and 30.7% of exclusions from each trial were due to eligibility criteria excluding those with high or uncontrolled blood pressure. Frailty (odds ratio [OR] =.44; 95%CI =.36–.54 [OPTiMISE]), cardiovascular polypharmacy (OR =.61; 95%CI =.55–.68 [SPRINT]) and multimorbidity (OR =.72; 95%CI =.64–.82 [SPRINT]) were associated with a lower likelihood of being eligible for one or more of the trials. CONCLUSION: A possible unintended consequence of blood pressure criteria used by trials attempting to answer different primary questions is that for many older patients, no trial evidence exists to inform treatment decisions in routine practice. Caution should be exercised when applying results from existing trials to patients with frailty or multimorbidity.

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

Modern general practice is complex. Issues such as multimorbidity, polypharmacy and chronic illness management can make applying myriad single condition evidence-based guidelines increasingly difficult. This is compounded because the problems presented in general practice often require both clinical and social solutions. In response to these issues, generalist clinicians are now expected to practise 'person-centred care': enabling and empowering patients by combining the technical rationality of medical science with individual values, needs and preferences. To explore this difficult undertaking we conducted an ethnography of a general practice surgery in England, including participant observation, interviews, and focus groups with patients, clinicians, and support staff, from February 2018 to March 2019. Our findings suggest that clinicians in our study faced considerable constraints, broadly conceived as the limits of biomedicine and the structural constraints of general practice. However, they mitigated these by getting into good habits, which we conceive in two categories: using expert judgement and taking patients seriously. We further propose that clinicians did not merely will themselves towards these good habits but developed and adapted them by intuitively adopting a second-order 'meta' habit of enaction - treating each consultation as collaboratively co-created anew. This suggests an important feature of the general practice consultation: it is conducted as much in the subjunctive as the indicative mood. Developing this proposition, we propose a more general form of medical practice - subjunctive medicine - extolling the value of the co-created social order of the general practice consultation itself. We suggest that practising subjunctive medicine may help clinicians sustainably and resiliently achieve the aims of person-centred care in modern general practice.

Chronic kidney disease (CKD) is defined as any abnormality of kidney function or structure with implications for health that is present for more than 3 months. It is classified according to the estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR). The presence of an eGFR 90 days is diagnostic of CKD. CKD is common. Data from the 2016 Health Survey of England reveal that 15% of people aged ≥35 years have CKD (stage 1 to 5), with 7% in CKD stages 3 to 5.1 An important minority of people with CKD will progress to end-stage renal disease and require renal replacement therapy, but the greatest significance of CKD is as a powerful and potentially modifiable risk factor for cardiovascular disease (CVD). Large-scale robust epidemiological data indicate that the risks of both all-cause mortality and cardiovascular (CV) mortality in the general population increase with eGFR

Background There is debate as to what extent older patients (≥80 years) should be treated for high blood pressure. Existing trials show that blood pressure lowering in this population is effective at preventing stroke and heart failure but also results in an increased risk of adverse events. However, it has been suggested that these studies enrolled healthier patients, who are less representative of the general population and more likely to benefit from treatment. Purpose This study aimed to compare the characteristics of patients eligible for three blood pressure management trials and assess the likelihood of eligibility for each trial based on common characteristics of older patients. Methods Cross-sectional study of data extracted from the medical records of 15,376 patients aged ≥80 years, registered to 24 general practices in the south of England. Anonymised patient data relating to the eligibility criteria for two previous medication intensification trials (HYVET, SPRINT) and one medication reduction trial (OPTiMISE) were extracted. Patients eligible for each trial were defined according to criteria specified in each trial protocol. Descriptive statistics were used to define the characteristics of each trial population. A logistic regression model was constructed to estimate predictors of eligibility for each trial, with practice included as a random effect. Results Approximately 268 (1.7%), 5,290 (34.4%) and 3,940 (25.6%) patients were eligible for HYVET, SPRINT and OPTiMISE trials respectively. There was little overlap in eligibility for each trial (1.0% were eligible for HYVET and SPRINT; 0% were eligible for HYVET and OPTiMISE; 10.2% were eligible for SPRINT and OPTiMISE). Patients eligible for OPTiMISE were comparable to the general population in terms of frailty (eFI 0.12 [OPTiMISE] vs 0.11 [general population]), but had more morbidities (4 vs 3) and cardiovascular medications prescribed (4 vs 2). Patients in HYVET and SPRINT were less frail, multi-morbid and prescribed less cardiovascular medications. Overall, increasing frailty and a history of cardiovascular disease reduced the likelihood of being eligible for any trial. Conclusions Patients eligible for OPTiMISE appear to best represent the population aged ≥80 years attending UK primary care. Increasing frailty and/or multi-morbidity reduce the likelihood of eligibility for all three blood pressure trials. Caution should be exercised when applying the results from randomised controlled trials to management of blood pressure in frail and multi-morbid patients. Acknowledgement/Funding This study was funded by the National Institute for Health Research (NIHR) SPCR and Oxford CLAHRC

IntroductionCare home residents are at increased risk of infections and antibiotic prescription. Reduced antibiotic use from fewer infections would improve quality of life. TheProbiotics toReduceInfections iN CarEhome reSidentS(PRINCESS) trial aims to determine the efficacy and investigate mechanisms of daily probiotics on antibiotic use and incidence of infections in care home residents.Methods and analysisPRINCESS is a double-blind, individually randomised, placebo-controlled trial that will assess the effect of a daily oral probiotic combination ofLactobacillus rhamnosus,GG (LGG) andBifidobacterium animalissubsp.lactis, BB-12 (BB-12) on cumulative antibiotic administration days (CAADs) (primary outcome) for infection in up to 330 care home residents aged ≥65 years over up to 12 months. Secondary outcomes include:Infection:Total number of days of antibiotic administration for each infection type (respiratory tract infection, urinary tract infection, gastrointestinal infection, unexplained fever and other); number, site, duration of infection; estimation of incidence and duration of diarrhoea and antibiotic-associated diarrhoea;Stool microbiology:Clostridium difficileinfection; Gram-negative Enterobacteriaceae and vancomycin-resistant enterococci; LGG and BB-12.Oral microbiology: Candidaspp.Health and well-being:Self and/or proxy health-related quality of life EQ5D (5 L); self-and/or proxy-reported ICEpop CAPability measure for older people.Hospitalisations:number and duration of all-cause hospital stays.Mortality:deaths.Mechanistic immunology outcomes:influenza vaccine efficacy (haemagglutination inhibition assay and antibody titres); full blood count and immune cell phenotypes, plasma cytokines and chemokines; cytokine and chemokine response in whole blood stimulatedex vivoby toll-like receptor 2 and 4 agonists; monocyte and neutrophil phagocytosis ofEscherichia coli; serum vitamin D.Ethics and disseminationEthics approval is from the Wales Research Ethics Committee 3. Findings will be disseminated through peer-reviewed journals and conferences; results will be of interest to patient and policy stakeholders.Trial registration numberISRCTN16392920; Pre-results.

PURPOSE: Presentation with acute lower respiratory tract infection (LRTI) in primary care is common. The aim of this study was to help clinicians treat patients presenting with LRTI in primary care by identifying those at risk of serious adverse outcomes (death, admission, late-onset pneumonia). METHODS: In a prospective cohort study of patients presenting with LRTI symptoms, patient characteristics and clinical findings were recorded and adverse events identified over 30 days by chart review. Multivariable logistic regression analyses identified predictors of adverse outcomes. RESULTS: Participants were recruited from 522 UK practices in 2009-2013. The analysis was restricted to the 28,846 adult patients not referred immediately to the hospital. Serious adverse outcomes occurred in 325/28,846 (1.1%). Eight factors were independently predictive; these characterized symptom severity (absence of coryza, fever, chest pain, and clinician-assessed severity), patient vulnerability (age >65 years, comorbidity), and physiological impact (oxygen saturation

BACKGROUND: Atrial Fibrillation is the most common arrhythmia worldwide with a global age adjusted prevalence of 0.5% in 2010. Anticoagulation treatment using warfarin or direct oral anticoagulants is effective in reducing the risk of AF-related stroke by approximately two-thirds and can provide a 10% reduction in overall mortality. There has been increased interest in detecting AF due to its increased incidence and the possibility to prevent AF-related strokes. Inexpensive consumer devices which measure the ECG may have the potential to accurately detect AF but do not generally incorporate diagnostic algorithms. Machine learning algorithms have the potential to improve patient outcomes particularly where diagnoses are made from large volumes or complex patterns of data such as in AF.METHODS: We designed a novel AF detection algorithm using a de-correlated Lorenz plot of 60 consecutive RR intervals. In order to reduce the volume of data, the resulting images were compressed using a wavelet transformation (JPEG200 algorithm) and the compressed images were used as input data to a Support Vector Machine (SVM) classifier. We used the Massachusetts Institute of Technology (MIT)-Beth Israel Hospital (BIH) Atrial Fibrillation database and the MIT-BIH Arrhythmia database as training data and verified the algorithm performance using RR intervals collected using an inexpensive consumer heart rate monitor device (Polar-H7) in a case-control study.RESULTS: The SVM algorithm yielded excellent discrimination in the training data with a sensitivity of 99.2% and a specificity of 99.5% for AF. In the validation data, the SVM algorithm correctly identified AF in 79/79 cases; sensitivity 100% (95% CI 95.4%-100%) and non-AF in 328/336 cases; specificity 97.6% (95% CI 95.4%-99.0%).CONCLUSIONS: An inexpensive wearable heart rate monitor and machine learning algorithm can be used to detect AF with very high accuracy and has the capability to transmit ECG data which could be used to confirm AF. It could potentially be used for intermittent screening or continuously for prolonged periods to detect paroxysmal AF. Further work could lead to cost-effective and accurate estimation of AF burden and improved risk stratification in AF.