Effect of corticosteroid therapy on influenza-related mortality: a systematic review and meta-analysis

Background: Most studies have reported that corticosteroid therapy adversely influences influenza-related outcomes. Methods: Electronic databases were searched from inception to March 2013 for experimental and observational studies investigating systemic corticosteroid therapy for presumed influenza-associated complications. Meta-analysis of Observational Studies in Epidemiology guidelines were adopted. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects models, and heterogeneity was assessed using the I2 statistic. Quality of evidence was assessed using the Grading Assessment, Development, and Evaluation system. Results: We identified 16 eligible studies (3039 individuals), all of which were observational; 10 (1497 individuals) were included in the meta-analysis of mortality, of which 9 studied patients with 2009 pandemic influenza A virus subtype H1N1. Risk of bias was greatest in the comparability domain of the Newcastle–Ottawa scale, consistent with potential confounding by indication, and data specific to mortality were of low quality. Meta-analysis found an increased odds of mortality (OR, 2.12; 95% CI, 1.36–3.29) associated with corticosteroid therapy. Subgroup analysis of adjusted estimates from 4 studies with very low statistical heterogeneity found a similar association (OR, 2.58; 95% CI, 1.39–4.79). Conclusions: No completed clinical trials were identified. Evidence from observational studies, with important limitations, suggests that corticosteroid therapy for presumed influenza-associated complications is associated with increased mortality

Contrastive Deep Encoding Enables Uncertainty-aware Machine-learning-assisted Histopathology

Deep neural network models can learn clinically relevant features from millions of histopathology images. However generating high-quality annotations to train such models for each hospital, each cancer type, and each diagnostic task is prohibitively laborious. On the other hand, terabytes of training data -- while lacking reliable annotations -- are readily available in the public domain in some cases. In this work, we explore how these large datasets can be consciously utilized to pre-train deep networks to encode informative representations. We then fine-tune our pre-trained models on a fraction of annotated training data to perform specific downstream tasks. We show that our approach can reach the state-of-the-art (SOTA) for patch-level classification with only 1-10% randomly selected annotations compared to other SOTA approaches. Moreover, we propose an uncertainty-aware loss function, to quantify the model confidence during inference. Quantified uncertainty helps experts select the best instances to label for further training. Our uncertainty-aware labeling reaches the SOTA with significantly fewer annotations compared to random labeling. Last, we demonstrate how our pre-trained encoders can surpass current SOTA for whole-slide image classification with weak supervision. Our work lays the foundation for data and task-agnostic pre-trained deep networks with quantified uncertainty.Comment: 18 pages, 8 figure

Corticosteroids as Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and Meta-analysis

Objective: Corticosteroids may be beneficial in sepsis but uncertainty remains over their effects in severe influenza. This systematic review updates the current evidence regarding corticosteroids in the treatment of influenza and examines the effect of dose on outcome.Data Sources: Electronic databases (MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL, Web of Science) and trial registries were searched to October 2018 for randomised controlled trials (RCTs), quasi-experimental designs and observational cohort studies reporting corticosteroid versus no corticosteroid treatment in individuals with influenza. Study Selection and Data Extraction:Two researchers independently assessed studies for inclusion. Risk of bias was assessed using the Cochrane Risk of Bias tool (RCTs) or Newcastle-Ottawa Scale (observational studies). Where appropriate, we estimated the effect of corticosteroids by random effects meta-analyses using the generic inverse variance method. Meta‐regression analysis was used to assess the association of corticosteroid dose and mortality. Data Synthesis: We identified 30 eligible studies, all observational apart from one RCT. Twenty-one observational studies were included in the meta-analysis of mortality, which suggested an adverse association with corticosteroid therapy (Odds ratio (OR) 3.90, 95% confidence interval (CI) 2.31 to 6.60, 15 studies; adjusted hazard ratio 1.49, 95% CI 1.09 to 2.02, 6 studies). Risk of bias assessment was consistent with potential confounding by indication. Pooled analysis of seven studies showed increased odds of hospital-acquired infection in people treated with corticosteroids (unadjusted OR 2.74, 95% CI 1.51 to 4.95). Meta-regression of the effect of dose on mortality did not reveal an association, but reported doses of corticosteroids in included studies were high (mostly >40 mg methylprednisolone (or equivalent) per day).Conclusions:Corticosteroid treatment in influenza is associated with increased mortality and hospital-acquired infection, but the evidence relates mainly to high corticosteroid doses and is of low quality with potential confounding by indication a major concern.

13-Valent vaccine serotype pneumococcal community acquired pneumonia in adults in high clinical risk groups

There is debate regarding the value of vaccinating adults with the 13-valent pneumococcal conjugate vaccine (PCV-13). This analysis was conducted to investigate the risk of PCV-13 serotype community acquired pneumonia (CAP) in hospitalised adults with co-morbid disease and risk factors for pneumococcal disease in the UK. Consecutive adults hospitalised (2008-2013) with a primary diagnosis of CAP, were recruited. Pneumococcal aetiology disease was identified by use of pneumococcal urinary antigen detection and serotype identification using a validated multiplex immunoassay or serum latex agglutination. Adults with PCV-13 serotype CAP were compared to those with non-PCV-13 serotype CAP. Of 2224 patients, PCV-13 serotype CAP was identified in 337 (15.2%) and non-PCV-13 serotype CAP in 250 (11.2%) individuals. Adults aged >/=65years with one or more clinical risk factors had a significantly lower risk of PCV-13 serotype CAP compared to those aged 16-64years without clinical risk factors (aOR 0.61, 95%CI 0.41-0.92, p=.018). In a stacked-risk analysis, the presence of incremental clinical risk factors was associated with lower odds of PCV-13 disease (p for trend=.029) Adults with underlying chronic respiratory disease (aOR) 0.56, 95% CI 0.36-0.85, p=.007) and chronic kidney disease (aOR 0.48, 95% CI 0.25-0.92, p=.028) had significantly lower adjusted odds of PCV-13 compared to non-PCV-13 serotype CAP. This analysis suggests that in the UK, the burden of PCV13 disease is greater in adults outside the traditional 'at-risk' groups compared to adults in 'at-risk' groups

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against vaccine serotype pneumococcal pneumonia in adults: A case-control test-negative design study.

BACKGROUND: Vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is available in the United Kingdom to adults aged 65 years or older and those in defined clinical risk groups. We evaluated the vaccine effectiveness (VE) of PPV23 against vaccine-type pneumococcal pneumonia in a cohort of adults hospitalised with community-acquired pneumonia (CAP). METHODS AND FINDINGS: Using a case-control test-negative design, a secondary analysis of data was conducted from a prospective cohort study of adults (aged ≥16 years) with CAP hospitalised at 2 university teaching hospitals in Nottingham, England, from September 2013 to August 2018. The exposure of interest was PPV23 vaccination at any time point prior to the index admission. A case was defined as PPV23 serotype-specific pneumococcal pneumonia and a control as non-PPV23 serotype pneumococcal pneumonia or nonpneumococcal pneumonia. Pneumococcal serotypes were identified from urine samples using a multiplex immunoassay or from positive blood cultures. Multivariable logistic regression was used to derive adjusted odds of case status between vaccinated and unvaccinated individuals; VE estimates were calculated as (1 - odds ratio) × 100%. Of 2,357 patients, there were 717 PPV23 cases (48% vaccinated) and 1,640 controls (54.5% vaccinated). The adjusted VE (aVE) estimate against PPV23 serotype disease was 24% (95% CI 5%-40%, p = 0.02). Estimates were similar in analyses restricted to vaccine-eligible patients (n = 1,768, aVE 23%, 95% CI 1%-40%) and patients aged ≥65 years (n = 1,407, aVE 20%, 95% CI -5% to 40%), but not in patients aged ≥75 years (n = 905, aVE 5%, 95% CI -37% to 35%). The aVE estimate in relation to PPV23/non-13-valent pneumococcal conjugate vaccine (PCV13) serotype pneumonia (n = 417 cases, 43.7% vaccinated) was 29% (95% CI 6%-46%). Key limitations of this study are that, due to high vaccination rates, there was a lack of power to reject the null hypothesis of no vaccine effect, and that the study was not large enough to allow robust subgroup analysis in the older age groups. CONCLUSIONS: In the setting of an established national childhood PCV13 vaccination programme, PPV23 vaccination of clinical at-risk patient groups and adults aged ≥65 years provided moderate long-term protection against hospitalisation with PPV23 serotype pneumonia. These findings suggest that PPV23 vaccination may continue to have an important role in adult pneumococcal vaccine policy, including the possibility of revaccination of older adults

Diverse Single Image Generation with Controllable Global Structure through Self-Attention

Image generation from a single image using generative adversarial networks is quite interesting due to the realism of generated images. However, recent approaches need improvement for such realistic and diverse image generation, when the global context of the image is important such as in face, animal, and architectural image generation. This is mainly due to the use of fewer convolutional layers for mainly capturing the patch statistics and, thereby, not being able to capture global statistics very well. We solve this problem by using attention blocks at selected scales and feeding a random Gaussian blurred image to the discriminator for training. Our results are visually better than the state-of-the-art particularly in generating images that require global context. The diversity of our image generation, measured using the average standard deviation of pixels, is also better

野海・山田方程式系のWKB解析に向けて (微分方程式の変形と漸近解析)

Child contact is a recognised risk factor for adult pneumococcal disease. Peaks in invasive pneumococcal disease incidence observed during winter holidays may be related to changes in social dynamics. This analysis was conducted to examine adult pneumococcal community-acquired pneumonia (CAP) incidence during school holiday periods.Between September 2008 and 2013, consecutive adults admitted to hospitals covering the Greater Nottingham area with a diagnosis of CAP were studied. Pneumococcal pneumonia was detected using culture and antigen detection methods.Of 2221 adults studied, 575 (25.9%) were admitted during school holidays and 643 (29.0%) had pneumococcal CAP. CAP of pneumococcal aetiology was significantly more likely in adults admitted during school holidays compared to term time (35.3% versus 26.7%; adjusted OR 1.38, 95% CI 1.11–1.72, p=0.004). Over the 5-year period, the age-adjusted incidence of hospitalised pneumococcal CAP was higher during school holidays compared to term time (incident rate ratio 1.35, 95% CI 1.14–1.60, p<0.001); there was no difference in rates of all-cause CAP or non-pneumococcal CAP. Reported child contact was higher in individuals with pneumococcal CAP admitted during school holidays compared to term time (42.0% versus 33.7%, OR 1.43, 95% CI 1.00–2.03, p=0.046).Further study of transmission dynamics in relation to these findings and to identify appropriate intervention strategies is warranted.School holiday periods are associated with an increased incidence of adult pneumococcal community-acquired pneumonia http://ow.ly/JiAb3089Gii%U http://openres.ersjournals.com/content/erjor/3/1/00100-2016.full.pd

British Thoracic Society community-acquired pneumonia care bundle: results of a national implementation project.

In 2013, 16 U.K. hospital trusts participated in a quality improvement programme involving implementation of a community-acquired pneumonia (CAP) care bundle. High-level data were collected on 14,962 patients admitted with CAP; bundle implementation increased from 1% in October 2012 to 20% by September 2013. Analysis of patient-level data on 2118 adults (median age 75.3 years) found that in the bundle-implementation group, significantly more patients received antibiotics within 4 h of admission (adjusted OR 1.52, 95% CI 1.08 to 2.14, p=0.016) and 30-day inpatient mortality was lower (8.8% vs. 13.6%; adjusted OR 0.59, 95% CI 0.37 to 0.95, p=0.03)

Corticosteroids as adjunctive therapy in the treatment of influenza

BackgroundSpecific treatments for influenza are limited to neuraminidase inhibitors and adamantanes. Corticosteroids show evidence of benefit in sepsis and related conditions, most likely due to their anti?inflammatory and immunomodulatory properties. Although commonly prescribed for severe influenza, there is uncertainty over their potential benefits or harms. This is an update of a review first published in 2016. ObjectivesTo systematically assess the effectiveness and potential adverse effects of corticosteroids as adjunctive therapy in the treatment of influenza, taking into account differences in timing and doses of corticosteroids. Search methodsWe searched CENTRAL (2018, Issue 9), which includes the Cochrane Acute Respiratory infections Group's Specialised Register, MEDLINE (1946 to October week 1, 2018), Embase (1980 to 3 October 2018), CINAHL (1981 to 3 October 2018), LILACS (1982 to 3 October 2018), Web of Science (1985 to 3 October 2018), abstracts from the last three years of major infectious disease and microbiology conferences, and references of included articles. We also searched the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and the ISRCTN registry on 3 October 2018. Selection criteriaWe included randomised controlled trials (RCTs), quasi?RCTs, and observational studies that compared corticosteroid treatment with no corticosteroid treatment for influenza or influenza?like illness. We did not restrict studies by language of publication, influenza subtypes, clinical setting, or age of participants. We selected eligible studies in two stages: sequential examination of title and abstract, followed by full text. Data collection and analysisTwo review authors independently extracted data and assessed risk of bias. We pooled estimates of effect using a random?effects model, where appropriate. We assessed heterogeneity using the I2 statistic and assessed the certainty of the evidence using the GRADE framework. Main resultsThis updated review includes 30 studies (one RCT with two arms and 29 observational studies) with a total of 99,224 participants. We included 19 studies in the original review (n = 3459), all of which were observational, with 13 studies included in the meta?analysis for mortality. We included 12 new studies in this update (one RCT and 11 observational studies), and excluded one study in the original review as it has been superceded by a more recent analysis. Twenty?one studies were included in the meta?analysis (9536 individuals), of which 15 studied people infected with 2009 influenza A H1N1 virus (H1N1pdm09). Data specific to mortality were of very low quality, based predominantly on observational studies, with inconsistent reporting of variables potentially associated with the outcomes of interest, differences between studies in the way in which they were conducted, and with the likelihood of potential confounding by indication. Reported doses of corticosteroids used were high, and indications for their use were not well reported. On meta?analysis, corticosteroid therapy was associated with increased mortality (odds ratio (OR) 3.90, 95% confidence interval (CI) 2.31 to 6.60; I2 = 68%; 15 studies). A similar increase in risk of mortality was seen in a stratified analysis of studies reporting adjusted estimates (OR 2.23, 95% CI 1.54 to 3.24; I2 = 0%; 5 studies). An association between corticosteroid therapy and increased mortality was also seen on pooled analysis of six studies which reported adjusted hazard ratios (HRs) (HR 1.49, 95% CI 1.09 to 2.02; I2 = 69%). Increased odds of hospital?acquired infection related to corticosteroid therapy were found on pooled analysis of seven studies (pooled OR 2.74, 95% CI 1.51 to 4.95; I2 = 90%); all were unadjusted estimates, and we graded the data as of very low certainty. Authors' conclusionsWe found one RCT of adjunctive corticosteroid therapy for treating people with community?acquired pneumonia, but the number of people with laboratory?confirmed influenza in the treatment and placebo arms was too small to draw conclusions regarding the effect of corticosteroids in this group, and we did not include it in our meta?analyses of observational studies. The certainty of the available evidence from observational studies was very low, with confounding by indication a major potential concern. Although we found that adjunctive corticosteroid therapy is associated with increased mortality, this result should be interpreted with caution. In the context of clinical trials of adjunctive corticosteroid therapy in sepsis and pneumonia that report improved outcomes, including decreased mortality, more high?quality research is needed (both RCTs and observational studies that adjust for confounding by indication). The currently available evidence is insufficient to determine the effectiveness of corticosteroids for people with influenza