The impact of therapeutics on mortality in hospitalised patients with COVID-19:systematic review and meta-analyses informing the European Respiratory Society living guideline

Hospitalised patients with coronavirus disease 2019 (COVID-19) have a high mortality rate. There are an increasing number of published randomised controlled trials for anti-inflammatory, anti-viral and other treatments. The European Respiratory Society Living Guidelines for the Management of Hospitalised Adults with COVID-19 were published recently, providing recommendations on appropriate pharmacotherapy.Patient, Intervention, Comparator and Outcomes questions for key interventions were identified by an international panel and systematic reviews were conducted to identify randomised controlled trials meeting the inclusion criteria. The importance of end-points were rated, and mortality was identified as the key "critical" outcome for all interventions. Random-effects meta-analysis was used to pool studies and provide effect estimates for the impact of treatments on mortality.Corticosteroids, hydroxychloroquine, azithromycin, remdesivir, anti-interleukin (IL)-6 monoclonal antibodies, colchicine, lopinavir/ritonavir and interferon-β have been reviewed.Our results found further evidence in support of the use of corticosteroids, particularly dexamethasone, and anti-IL-6 receptor monoclonal antibody therapy. These data support the need to identify additional therapies with beneficial effects on mortality

Methods for the thematic synthesis of qualitative research in systematic reviews

<p>Abstract</p> <p>Background</p> <p>There is a growing recognition of the value of synthesising qualitative research in the evidence base in order to facilitate effective and appropriate health care. In response to this, methods for undertaking these syntheses are currently being developed. Thematic analysis is a method that is often used to analyse data in primary qualitative research. This paper reports on the use of this type of analysis in systematic reviews to bring together and integrate the findings of multiple qualitative studies.</p> <p>Methods</p> <p>We describe thematic synthesis, outline several steps for its conduct and illustrate the process and outcome of this approach using a completed review of health promotion research. Thematic synthesis has three stages: the coding of text 'line-by-line'; the development of 'descriptive themes'; and the generation of 'analytical themes'. While the development of descriptive themes remains 'close' to the primary studies, the analytical themes represent a stage of interpretation whereby the reviewers 'go beyond' the primary studies and generate new interpretive constructs, explanations or hypotheses. The use of computer software can facilitate this method of synthesis; detailed guidance is given on how this can be achieved.</p> <p>Results</p> <p>We used thematic synthesis to combine the studies of children's views and identified key themes to explore in the intervention studies. Most interventions were based in school and often combined learning about health benefits with 'hands-on' experience. The studies of children's views suggested that fruit and vegetables should be treated in different ways, and that messages should not focus on health warnings. Interventions that were in line with these suggestions tended to be more effective. Thematic synthesis enabled us to stay 'close' to the results of the primary studies, synthesising them in a transparent way, and facilitating the explicit production of new concepts and hypotheses.</p> <p>Conclusion</p> <p>We compare thematic synthesis to other methods for the synthesis of qualitative research, discussing issues of context and rigour. Thematic synthesis is presented as a tried and tested method that preserves an explicit and transparent link between conclusions and the text of primary studies; as such it preserves principles that have traditionally been important to systematic reviewing.</p

Clinical examination for hyperlinear palms to determine filaggrin genotype:a diagnostic test accuracy study

BackgroundPalmar hyperlinearity is a feature of ichthyosis vulgaris, the monogenic skin disorder caused by FLG loss-of-function mutations.ObjectiveTo investigate how well the presence or absence of hyperlinear palms (HLP) detect FLG genotype in children.MethodsSTARD criteria are used to report this diagnostic accuracy study. Phenotype and genotype data (four most prevalent FLG null mutations) were obtained from a total of 3656 children in three studies: the UK CLOTHES trial (children 1–5 years with moderate–severe atopic eczema); UK BEEP trial (2 year olds at high risk of developing atopic eczema); UK-Irish eczema case collection (0–16 year olds with atopic eczema). All participants included in analyses of HLP as the index test and FLG genotype as the reference were of white European ancestry.ResultsThirty-two percent of participants (1159/3656) had FLG null mutation(s) and 37% (1347/3656) had HLP. In 13% (464/3656), HLP was recorded as ‘unsure’ or not recorded. The sensitivity and specificity of HLP for detecting FLG mutations in each of the studies was: 67% (95% CI 55–78%) and 75% (67–82%) in CLOTHES; 46% (36–55%) and 89% (86–91%) in BEEP; 72% (68–75%) and 60% (57–62%) in the UK-Irish case collection. Positive and negative likelihood ratios were: 2.73 (1.95–3.81) and 0.44 (0.31–0.62) in CLOTHES; 4.02 (2.99–5.40) and 0.61 (0.52–0.73) in BEEP; 1.79 (1.66–1.93) and 0.47 (0.42–0.53) in the UK-Irish collection.DiscussionTrained observers were able to define palmar hyperlinearity in the majority (3191/3656, 87%) of cases. The presence of HLP is not a reliable sign to detect FLG mutations, but the absence of HLP excludes FLG null genotype with a reasonable degree of certainty

Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.

BACKGROUND: Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children. METHODS: We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment. FINDINGS: 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09). INTERPRETATION: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn. FUNDING: National Institute for Health Research Health Technology Assessment

Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.

BACKGROUND: Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children. METHODS: We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment. FINDINGS: 1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09). INTERPRETATION: We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn. FUNDING: National Institute for Health Research Health Technology Assessment

Scoping the international impact from four independent national dermatology trials

Background: Research impact describes whether and how research results in wider benefits to society beyond academic publication. Little is known about translation of clinical trial research into dermatological practice. Aim: We scoped international impact from four independently funded clinical trials published by our group over the past 10years. Methods: This was a scoping survey of 35 international colleagues from 22 countries followed by a narrative summary of emergent themes. Results: All recipients kindly responded to the survey. At least 20 emergent themes were identified, which broadly included: (i) interest and enthusiasm in the concept of trying to document clinical trial impact; (ii) direct impacts such as adoption of the drug as tested and recommended from the trial results, including more confidence using the drug in slightly different ways for the same condition; (iii) the finding that trial impact was dependent on factors such as drug availability and country-specific disease patterns; and (iv) the educational value of good trial design for journal club discussions and improving future clinical trial designs in dermatology. Our survey suggests that uptake into clinical practice was surprisingly rapid and widespread. Conclusion: Clinical trial research is of little use unless findings are translated into clinical practice for patient benefit. Our international scoping survey suggests that independent clinical trials that address important questions identified by the dermatology community have substantial, diverse and far-reaching impacts on dermatological practice

Relationship between Symptoms, Exacerbations, and Treatment Response in Bronchiectasis

RATIONALE: Bronchiectasis guidelines regard treatment to prevent exacerbation and treatment of daily symptoms as separate objectives. OBJECTIVE: We hypothesized that patients with greater symptoms would be at higher risk of exacerbations and therefore a treatment aimed at reducing daily symptoms would also reduce exacerbations in highly symptomatic patients. METHODS: An observational cohort of 333 patients from the East of Scotland(2012-2016). Symptoms were either modelled as a continuous variable or patients were classified as high, moderate and low symptom burden(&gt;70, 40-70 and &lt;40 using the SGRQ symptom score). We hypothesised that exacerbation would be reduced in highly symptomatic patients. This was tested in a post-hoc analysis of a randomized trial of inhaled mannitol (N=461 patients) Measurement and Main Results: In the observational cohort daily symptoms were a significant predictor of future exacerbations (rate ratio [RR] 1.10, 95% confidence interval[CI] 1.03-1.17, P=0.005). Patients with high symptom scores had higher exacerbation rates (RR 1.74, 95% CI 1.12-2.72,P=0.01) over 12 months follow-up compared to those with lower symptoms. Inhaled mannitol treatment improved the time to first exacerbation (hazard ratio [HR] 0.56; 95% CI 0.40-0.77; P&lt;0.001) and the proportion of patients remaining exacerbation free for 12 months treatment was higher in the mannitol group (32.7% vs. 14.6%; RR 2.84, 95% CI 1.40-5.76; P=0.003) only in highly symptomatic patients. In contrast no benefit was evident in patients with lower symptom burden. CONCLUSIONS: Highly symptomatic patients are at increased risk of exacerbations, and exacerbation benefit with inhaled mannitol was only evident in patients with high symptom burden

The impact of acute air pollution fluctuations on bronchiectasis pulmonary exacerbation:A case-crossover analysis

In bronchiectasis, exacerbations are believed to be triggered by infectious agents, but often no pathogen can be identified. We hypothesised that acute air pollution exposure may be associated with bronchiectasis exacerbations.We combined a case-crossover design with distributed lag models in an observational record linkage study. Patients were recruited from a specialist bronchiectasis clinic at Ninewells Hospital, Dundee, UK.We recruited 432 patients with clinically confirmed bronchiectasis, as diagnosed by high-resolution computed tomography. After excluding days with missing air pollution data, the final model for particles with a 50% cut-off aerodynamic diameter of 10 µm (PM; 10; ) was based on 6741 exacerbations from 430 patients and for nitrogen dioxide (NO; 2; ) it included 6248 exacerbations from 426 patients. For each 10 µg·m; -; ³ increase in PM; 10; and NO; 2; , the risk of having an exacerbation that same day increased significantly by 4.5% (95% CI 0.9-8.3) and 3.2% (95% CI 0.7-5.8) respectively. The overall (lag zero to four) increase in risk of exacerbation for a 10 μg·m; -3; increase in air pollutant concentration was 11.2% (95% CI 6.0-16.8) for PM; 10; and 4.7% (95% CI 0.1-9.5) for NO; 2; Subanalysis showed higher relative risks during spring (PM; 10; 1.198 (95% CI 1.102-1.303), NO; 2; 1.146 (95% CI 1.035-1.268)) and summer (PM; 10; 2.142 (95% CI 1.785-2.570), NO; 2; 1.352 (95% CI 1.140-1.602)) when outdoor air pollution exposure would be expected to be highest.In conclusion, acute air pollution fluctuations are associated with increased exacerbation risk in bronchiectasis