Analysis of exhaled breath to identify critically ill patients with ventilator-associated pneumonia.

Ventilator-associated pneumonia commonly occurs in critically ill patients. Clinical suspicion results in overuse of antibiotics, which in turn promotes antimicrobial resistance. Detection of volatile organic compounds in the exhaled breath of critically ill patients might allow earlier detection of pneumonia and avoid unnecessary antibiotic prescription. We report a proof of concept study for non-invasive diagnosis of ventilator-associated pneumonia in intensive care (the BRAVo study). Mechanically ventilated critically ill patients commenced on antibiotics for clinical suspicion of ventilator-associated pneumonia were recruited within the first 24 h of treatment. Paired exhaled breath and respiratory tract samples were collected. Exhaled breath was captured on sorbent tubes and then analysed using thermal desorption gas chromatography-mass spectrometry to detect volatile organic compounds. Microbiological culture of a pathogenic bacteria in respiratory tract samples provided confirmation of ventilator-associated pneumonia. Univariable and multivariable analyses of volatile organic compounds were performed to identify potential biomarkers for a 'rule-out' test. Ninety-six participants were enrolled in the trial, with exhaled breath available from 92. Of all compounds tested, the four highest performing candidate biomarkers were benzene, cyclohexanone, pentanol and undecanal with area under the receiver operating characteristic curve ranging from 0.67 to 0.77 and negative predictive values from 85% to 88%. Identified volatile organic compounds in the exhaled breath of mechanically ventilated critically ill patients show promise as a useful non-invasive 'rule-out' test for ventilator-associated pneumonia.

Position statement: The need for EU legislation to require disclosure and labelling of the composition of medical devices.

BACKGROUND: In recent years, skin reactions secondary to the use of medical devices (MD), such as allergic contact dermatitis have increasingly been observed (e.g. to continuous blood sugar monitoring systems, insulin pumps, wound dressings, medical gloves, etc.): this is regarded as a developing epidemic. Lack of labelling of the composition of MD, as well as frequent lack of cooperation of manufacturers to disclose this relevant information, even when contacted by the clinician for the individual case of an established adverse reaction, significantly impede patient care. OBJECTIVES: To advocate for full ingredient labelling in the implementation of EU regulation for MD. METHODS: This position paper reviews the scientific literature, the current regulatory framework adopted for MD to date, and the likely impact, including some costs data in case of the absence of such labelling. RESULTS: Efforts made by several scientific teams, who are trying to identify the culprit of such adverse effects, either via asking for cooperation from companies, or using costly chemical analyses of MD, can only partly, and with considerable delay, compensate for the absence of meaningful information on the composition of MD; hence, patient management is compromised. Indeed, without knowing the chemical substances present, physicians are unable to inform patients about which substances they should avoid, and which alternative MD may be suitable/tolerated. CONCLUSION: There is an urgent need for full and accurate labelling of the chemical composition of MD in contact with the human body.

The epidemic of methylisothiazolinone contact allergy in Europe: follow-up on changing exposures.

BACKGROUND: Methylisothiazolinone (MI) has caused an unprecedented epidemic of contact allergy in Europe and elsewhere. Subsequently, regulatory action has been taken, at least in Europe, aiming at reducing risk of MI sensitization. OBJECTIVE: To follow-up on the prevalence of contact allergy to MI in consecutively patch tested patients and assess the spectrum of products containing MI or methylchloroisothiazolinone (MCI)/MI in patients positive to MI which elicited current allergic contact dermatitis. METHODS: A cross-sectional survey was performed in 2016 and 2017, including all adult patients patch tested with the baseline series (including MI 0.2% aq.) between 1 May and 31 October at 14 centres in 11 European countries. Patients with positive reactions (+ to +++) to MI were further examined regarding history, clinical characteristics and eliciting products, which were categorized into 34 types and 4 classes (leave-on, rinse-off, household, occupational). The results were compared with the reference year 2015. RESULTS: A total of 317 patients, n = 202 of 4278 tested in 2016 (4.72%) and n = 115 of 3879 tested in 2017 (2.96%), had positive reactions to MI; the previous result from 2015 was 5.97% (P < 0.0001). The share of currently relevant contact allergy among all positive reactions declined significantly as well (P = 0.0032). Concerning product classes, a relative decline of leave-on and a relative increase of rinse-off and household products was noted. CONCLUSION: The prevalence of MI contact allergy decreased by 50% from 2015 to 2017. As a consequence of regulation, the share of cosmetics products (leave-on in particular) eliciting allergic contact dermatitis is decreasing. The chosen method of analysing causative products in sensitized patients has proven useful to monitor effects of intervention.

The cost-effectiveness of universal late-pregnancy screening for macrosomia in nulliparous women: a decision analysis.

OBJECTIVE: To identify the most cost-effective policy for detection and management of fetal macrosomia in late-stage pregnancy. DESIGN: Health economic simulation model. SETTING: All English NHS antenatal services. POPULATION: Nulliparous women in the third trimester treated within the UK NHS. METHODS: A health economic simulation model was used to compare long-term maternal-fetal health and cost outcomes for two detection strategies (universal ultrasound scanning at approximately 36 weeks of gestation versus selective ultrasound scanning), combined with three management strategies (planned caesarean section versus induction of labour versus expectant management) of suspected fetal macrosomia. Probabilities, costs and health outcomes were taken from literature. MAIN OUTCOME MEASURES: Expected costs to the NHS and quality-adjusted life-years (QALYs) gained from each strategy, calculation of net benefit and hence identification of most cost-effective strategy. RESULTS: Compared with selective ultrasound, universal ultrasound increased QALYs by 0.0038 (95% CI 0.0012-0.0076), but also costs by £123.50 (95% CI 99.6-149.9). Overall, the health gains were too small to justify the cost increase given current UK thresholds cost-effective policy was selective ultrasound coupled with induction of labour where macrosomia was suspected. CONCLUSIONS: The most cost-effective policy for detection and management of fetal macrosomia is selective ultrasound scanning coupled with induction of labour for all suspected cases of macrosomia. Universal ultrasound scanning for macrosomia in late-stage pregnancy is not cost-effective. TWEETABLE ABSTRACT: Universal late-pregnancy ultrasound screening for fetal macrosomia is not warranted.

What is the optimal systemic treatment of men with metastatic, hormone-naive prostate cancer? A STOPCAP systematic review and network meta-analysis.

Background: Our prior Systemic Treatment Options for Cancer of the Prostate systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen-deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was carried out based on aggregate data (AD) from all available studies. Methods: Overall survival (OS) and failure-free survival data from completed Systemic Treatment Options for Cancer of the Prostate reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was OS. Correlations between treatment comparisons within one multi-arm, multi-stage trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed. Results: We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for AAP [hazard ration (HR) = 0.61, 95% confidence interval (CI) 0.53-0.71], Doc (HR = 0.77, 95% CI 0.68-0.87), ZA + Cel (HR = 0.78, 95% CI 0.62-0.97), ZA + Doc (HR = 0.79, 95% CI 0.66-0.94), Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and failure-free survival (100% probability). Doc was the second-best treatment of OS (35% probability). Conclusions: Uniquely, we have included all available results and appropriately accounted for inclusion of multi-arm, multi-stage trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with metastatic hormone-naive prostate cancer. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Patch testing with the European baseline series fragrance markers: a 2016 update.

BACKGROUND: Fragrance contact allergy is common and is currently screened for using the following European baseline series fragrance markers: fragrance mix (FM)I, FMII, Myroxylon pereirae and hydroxyisohexyl 3-cyclohexene carboxaldehyde. OBJECTIVES: To investigate the validity of patch testing using these fragrance markers in detecting fragrance allergy to 26 individual fragrance substances for which cosmetic ingredient labelling is mandatory within the European Union. METHODS: We conducted a retrospective review of the patch test records of all patients with eczema who underwent testing using the European baseline series, extended with the individual fragrance substances during the period from 2015 to 2016. RESULTS: Overall, 359 patients (17·2%) reacted to one or more allergens from the labelled fragrance substance series and/or a fragrance marker from the European baseline series. The allergens that were positive with the greatest frequencies were oxidized linalool [n = 154; 7·4%, 95% confidence interval (CI) 6·3-8·6], oxidized limonene (n = 89; 4·3%, 95% CI 3·4-5·2) and Evernia furfuracea (n = 44; 2·1%, 95% CI 1·5-2·8). Of the 319 patients who reacted to any of the labelled fragrance substances, only 130 (40·8%) also reacted to a baseline series fragrance marker. The sensitivity of our history-taking for detecting fragrance allergy was 25·7%. CONCLUSIONS: Given the evolving trends in fragrance allergy, patch testing with FMI, FMII, M. pereirae and hydroxyisohexyl 3-cyclohexene carboxaldehyde is no longer sufficient for screening for fragrance allergy.

Computationally efficient methods for fitting mixed models to electronic health records data.

Motivated by two case studies using primary care records from the Clinical Practice Research Datalink, we describe statistical methods that facilitate the analysis of tall data, with very large numbers of observations. Our focus is on investigating the association between patient characteristics and an outcome of interest, while allowing for variation among general practices. We explore ways to fit mixed-effects models to tall data, including predictors of interest and confounding factors as covariates, and including random intercepts to allow for heterogeneity in outcome among practices. We introduce (1) weighted regression and (2) meta-analysis of estimated regression coefficients from each practice. Both methods reduce the size of the dataset, thus decreasing the time required for statistical analysis. We compare the methods to an existing subsampling approach. All methods give similar point estimates, and weighted regression and meta-analysis give similar standard errors for point estimates to analysis of the entire dataset, but the subsampling method gives larger standard errors. Where all data are discrete, weighted regression is equivalent to fitting the mixed model to the entire dataset. In the presence of a continuous covariate, meta-analysis is useful. Both methods are easy to implement in standard statistical software.

A dynamic landscape of allergen associations in delayed-type cutaneous hypersensitivity.

BACKGROUND: Delayed-type hypersensitivity represents a significant clinical and public health challenge. Patients undergoing patch testing may exhibit positive reactions to more than one allergen. It is recognized that reactions to specific pairs of allergens are associated, reflecting a combination of exposure patterns and structural similarity. OBJECTIVES: To explore the influence of time of testing, age, sex and atopy status on allergen pair associations in a series of 45 110 consecutive patients tested over 30 years. METHODS: Patch test records of all patients undergoing testing with a modified European baseline series between 1985 and 2014 were retrieved from a database at St John's Institute of Dermatology. Reactions were read on days 2 and 4. For each allergen it was recorded whether the allergen was tested and whether the result was positive or negative. RESULTS: This is the largest reported study of patch test allergen pair relationships. Our analysis shows a high degree of variability in allergen pair associations. Rigorous statistical analysis reveals a large number of differences between groups, including a significant increase in the association between formaldehyde and multiple formaldehyde-releasing preservatives over the study period, in addition to pair associations with cobalt and formaldehyde-releasing preservatives. These were present to a significantly greater extent in men than in women. CONCLUSIONS: These observations extend our understanding of cutaneous allergy, with implications for both clinical practice and mechanisms of cutaneous hypersensitivity.

European Surveillance System on Contact Allergies (ESSCA): results with the European baseline series, 2013/14.

BACKGROUND: Contact allergy is a common condition and can severely interfere with daily life or professional activities. Due to changes in exposures, such as introduction of new substances, new products or formulations and regulatory intervention, the spectrum of contact sensitization changes. OBJECTIVE: To evaluate the current spectrum of contact allergy to allergens present in the European baseline series (EBS) across Europe. METHODS: Retrospective analysis of data collected by the European Surveillance System on Contact Allergies (ESSCA, www.essca-dc.org) in consecutively patch-tested patients, 2013/14, in 46 departments in 12 European countries. RESULTS: Altogether, 31 689 patients were included in the analysis. Compared to a similar analysis in 2004, the prevalence of contact allergy to methylisothiazolinone went up to around 20% in several departments. In comparison, contact allergy to the metals nickel, cobalt and chromium remained largely stable, at 18.1%, 5.9% and 3.2%, respectively, similar to mostly unchanged prevalence with fragrance mix I, II and Myroxylon pereirae (balsam of Peru) at 7.3%, 3.8% and 5.3%, respectively. In the subgroup of departments diagnosing (mainly) patients with occupational contact dermatitis, the prevalence of work-related contact allergies such as epoxy resin or rubber additives was found to be increased, compared to general dermatology departments. CONCLUSION: Continuous surveillance of contact allergy based on network data offers the identification of time trends or persisting problems, and thus enables focussing in-depth research (subgroup analyses, exposure analysis) on areas where it is needed.

Allowing for non-adherence to treatment in a randomized controlled trial of two antidepressants (citalopram versus reboxetine): an example from the GENPOD trial.

BACKGROUND: Meta-analyses suggest that reboxetine may be less effective than other antidepressants. Such comparisons may be biased by lower adherence to reboxetine and subsequent handling of missing outcome data. This study illustrates how to adjust for differential non-adherence and hence derive an unbiased estimate of the efficacy of reboxetine compared with citalopram in primary care patients with depression. METHOD: A structural mean modelling (SMM) approach was used to generate adherence-adjusted estimates of the efficacy of reboxetine compared with citalopram using GENetic and clinical Predictors Of treatment response in Depression (GENPOD) trial data. Intention-to-treat (ITT) analyses were performed to compare estimates of effectiveness with results from previous meta-analyses. RESULTS: At 6 weeks, 92% of those randomized to citalopram were still taking their medication, compared with 72% of those randomized to reboxetine. In ITT analysis, there was only weak evidence that those on reboxetine had a slightly worse outcome than those on citalopram [adjusted difference in mean Beck Depression Inventory (BDI) scores: 1.19, 95% confidence interval (CI) -0.52 to 2.90, p = 0.17]. There was no evidence of a difference in efficacy when differential non-adherence was accounted for using the SMM approach for mean BDI (-0.29, 95% CI -3.04 to 2.46, p = 0.84) or the other mental health outcomes. CONCLUSIONS: There was no evidence of a difference in the efficacy of reboxetine and citalopram when these drugs are taken and tolerated by depressed patients. The SMM approach can be implemented in standard statistical software to adjust for differential non-adherence and generate unbiased estimates of treatment efficacy for comparisons of two (or more) active interventions.

Allergic contact dermatitis: epidemiology, molecular mechanisms, in vitro methods and regulatory aspects. Current knowledge assembled at an international workshop at BfR, Germany.

Contact allergies are complex diseases, and one of the important challenges for public health and immunology. The German 'Federal Institute for Risk Assessment' hosted an 'International Workshop on Contact Dermatitis'. The scope of the workshop was to discuss new discoveries and developments in the field of contact dermatitis. This included the epidemiology and molecular biology of contact allergy, as well as the development of new in vitro methods. Furthermore, it considered regulatory aspects aiming to reduce exposure to contact sensitisers. An estimated 15-20% of the general population suffers from contact allergy. Workplace exposure, age, sex, use of consumer products and genetic predispositions were identified as the most important risk factors. Research highlights included: advances in understanding of immune responses to contact sensitisers, the importance of autoxidation or enzyme-mediated oxidation for the activation of chemicals, the mechanisms through which hapten-protein conjugates are formed and the development of novel in vitro strategies for the identification of skin-sensitising chemicals. Dendritic cell cultures and structure-activity relationships are being developed to identify potential contact allergens. However, the local lymph node assay (LLNA) presently remains the validated method of choice for hazard identification and characterisation. At the workshop the use of the LLNA for regulatory purposes and for quantitative risk assessment was also discussed.

Two-stage method to remove population- and individual-level outliers from longitudinal data in a primary care database.

PURPOSE: In the UK, primary care databases include repeated measurements of health indicators at the individual level. As these databases encompass a large population, some individuals have extreme values, but some values may also be recorded incorrectly. The challenge for researchers is to distinguish between records that are due to incorrect recording and those which represent true but extreme values. This study evaluated different methods to identify outliers. METHODS: Ten percent of practices were selected at random to evaluate the recording of 513,367 height measurements. Population-level outliers were identified using boundaries defined using Health Survey for England data. Individual-level outliers were identified by fitting a random-effects model with subject-specific slopes for height measurements adjusted for age and sex. Any height measurements with a patient-level standardised residual more extreme than ±10 were identified as an outlier and excluded. The model was subsequently refitted twice after removing outliers at each stage. This method was compared with existing methods of removing outliers. RESULTS: Most outliers were identified at the population level using the boundaries defined using Health Survey for England (1550 of 1643). Once these were removed from the database, fitting the random-effects model to the remaining data successfully identified only 75 further outliers. This method was more efficient at identifying true outliers compared with existing methods. CONCLUSIONS: We propose a new, two-stage approach in identifying outliers in longitudinal data and show that it can successfully identify outliers at both population and individual level. Copyright © 2011 John Wiley & Sons, Ltd.

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.

BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.

Excessive nickel release from earrings purchased from independent shops and street markets--a field study from Warsaw and London.

BACKGROUND: Nickel allergy is frequent and cause morbidity and increased health care costs. OBJECTIVE: The aim of this study was to determine the proportion of inexpensive earrings randomly purchased from stores and street markets in two capitals that gave positive dimethylglyoxime (DMG) test reactions and to determine whether the degree of nickel release was related to shop category. METHODS: Random inexpensive metallic earrings were purchased from stores and vendors in London and Warsaw. A qualitative investigation of nickel release by using the DMG test was performed. RESULTS: DMG testing revealed that respectively 15.1% (n=205) and 18.4% (n=206) of earrings purchased in London and Warsaw released nickel as indicated by positive test outcomes. Stratification by store category showed that DMG test-positive jewellery were mainly purchased from street markets and from stores that were not part of national or international chains. CONCLUSIONS: Despite the EU Nickel Directive having resulted in decreasing prevalence of nickel allergy, a large proportion of inexpensive earrings still release nickel in concentrations that may result in nickel allergy and dermatitis. Authorities should prioritize information campaigns and random inspections as a legislation that is not followed is of limited value.

Alcohol intake and risk of colorectal cancer: results from the UK Dietary Cohort Consortium.

BACKGROUND: Epidemiological studies have suggested that excessive alcohol intake increases colorectal cancer (CRC) risk. However, findings regarding tumour subsites and sex differences have been inconsistent. METHODS: We investigated the prospective associations between alcohol intake on overall and site- and sex-specific CRC risk. Analyses were conducted on 579 CRC cases and 1996 matched controls nested within the UK Dietary Cohort Consortium using standardised data obtained from food diaries as a main nutritional method and repeated using data from food frequency questionnaire (FFQ). RESULTS: Compared with individuals in the lightest category of drinkers (>0-<5 g per day), the multivariable odds ratios of CRC were 1.16 (95% confidence interval (95% CI): 0.88, 1.53) for non-drinkers, 0.91 (95% CI: 0.67, 1.24) for drinkers with 5-<15 g per day, 0.90 (95% CI: 0.65, 1.25) for drinkers with 15-<30 g per day, 1.02 (95% CI: 0.66, 1.58) for drinkers with 30-<45 g per day and 1.19 (95% CI: 0.75, 1.91) for drinkers with >or=45 g per day. No clear associations were observed between site-specific CRC risk and alcohol intake in either sex. Analyses using FFQ showed similar results. CONCLUSION: We found no significantly increased risk of CRC up to 30 g per day of alcohol intake within the UK Dietary Cohort Consortium.

Repeated exposure to hair dye induces regulatory T cells in mice.

BACKGROUND: We have recently shown that commercial p-phenylenediamine (PPD)-containing hair dyes are potent immune activators that lead to severe contact hypersensitivity in an animal model. However, only a minority of people exposed to permanent hair dyes develops symptomatic contact hypersensitivity. This suggests that the majority of people exposed to hair dyes does not become sensitized or develop immunological tolerance. OBJECTIVES: To study the immune response in mice repeatedly exposed to PPD-containing hair dye in a consumer-like manner. METHODS: A commercial hair dye containing PPD was tested in C57BL/6 mice. The local immune response was measured by ear swelling and by histological examinations. The immune response in the draining lymph nodes was analysed by flow cytometry. RESULTS: The hair dye induced local inflammation as seen by swelling and cell infiltration of the treated ears. In addition, exposure to hair dye caused T-cell activation as seen by T-cell proliferation and production of interferon-γ and interleukin (IL)-17 within the draining lymph nodes. The inflammatory response peaked at the fourth exposure to hair dye. From this point on, an upregulation of regulatory T cells and IL-10-producing cells was seen. CONCLUSIONS: This study shows that PPD-containing hair dyes strongly affect the immune system. In addition to being potent skin sensitizers that activate inflammatory T cells, hair dyes also induce anti-inflammatory mechanisms. This might explain why many consumers can use hair dyes repeatedly without developing noticeable allergies, but it also raises the question whether the immune modulatory effects of hair dyes might influence the development of autoimmune diseases and cancers.