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.

Intraoperative evaluation of colorectal anastomotic integrity: a comparison of air leak and dye leak tests.

BACKGROUND: Air leak tests (ALTs) and dye leak tests (DLTs) are the most common techniques for Intraoperative colorectal anastomosis assessment. The aim of our study was to compare the sensitivity of ALT with DLT in intraoperative evaluation of colorectal anastomotic integrity and to quantify the pressures routinely used in these tests. METHODS: A prospective clinical trial was conducted on patients who had elective colorectal resection and primary anastomosis from November 2017 until July 2019 in a single academic referral center. Each patient underwent both tests. The ALT was a transanal insufflation of CO2 and inspection of escaping bubbles around the anastomosis immersed in saline. The DLT was a transanal infusion of diluted methylene blue and inspection of dye stains on surgical gauze wrapping the anastomosis. Peak pressures were measured. Primary endpoints were the sensitivity of ALT and DLT in detecting intraoperative leaks, quantification of intraluminal pressure routinely used in these settings and assessment of postoperative complications such as a clinical leak. RESULTS: Forty patients underwent elective colorectal resection and anastomosis for malignant (67%) or benign n (33%) etiology. Height of anastomoses ranged from 1 to 25 cm (mean ± SD 12 ± 6 cm). Mean pressures measured were 26.5 ± 6.6 mmHg for the DLT and 22 ± 4 mmHg for the ALT (p < 0.01). Twenty percent of the DLTs were positive (8 patients) compared to 2.5% (1 patient) of the ALTs (RR 1.97, CI 1.2-2.7; p = 0.03). All patients who had positive tests had a suture reinforcement of the anastomosis. Only 1 patient, who had a positive DLT and ALT, developed a clinical leak CONCLUSIONS: DLT is more sensitive in detecting anastomotic leak intraoperatively. This is the first study measuring anastomotic tests' pressures used in-vivo in humans demonstrating a range of 20-30 mmHg. Based on our data we believe that a positive DLT with a negative ALT may be treated with suture reinforcement alone. CLINICAL TRIAL NUMBER: NCT03316677-10/17/2017.

Advances in local area optical data communication systems.

This paper reviews optical fibre technology for local area optical communications systems. Technologies used in local systems include single and multimode fibre, single and multimode lasers, optical modulators, photodetectors, wavelength division multiplexing, multilevel modulation formats, electronic packet switching, electronic equalization and error correction. These methods have enabled the local area optical link data rate to increase from 0.1 Gb s-1 in 1990 to nearly a Tb s-1 in 2019. The challenges to increasing link data rates further, while reducing the transmitted power per bit, at reduced cost are discussed. Potential technical solutions and newly proposed methods which might address these challenges are highlighted.

Carrierless amplitude and phase modulation in wireless visible light communication systems.

Visible light communications (VLCs) have attracted considerable interest in recent years owing to the potential to simultaneously achieve data transmission and illumination using low-cost light-emitting diodes (LEDs). However, the high-speed capability of such links is typically limited by the low bandwidth of LEDs. As a result, spectrally efficient advanced modulation formats have been considered for use in VLC links in order to mitigate this issue and enable higher data rates. Carrierless amplitude and phase (CAP) modulation is one such spectrally efficient scheme that has attracted significant interest in recent years owing to its good potential and practical implementation. In this paper, we introduce the basic features of CAP modulation and review its use in the context of indoor VLC systems. We describe some of its attributes and inherent limitations, present related advances aiming to improve its performance and potential and report on recent experimental demonstrations of LED-based VLC links employing CAP modulation. This article is part of the theme issue 'Optical wireless communication'.

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.

Earth-tide-induced fluctuations in the salinity of an inland river, New South Wales, Australia: a short-term study.

Wybong Creek discharges salts into the agriculturally and industrially important Hunter River in New South Wales, Australia. Abrupt increases in salinity occur periodically in the mid-Wybong Creek catchment. In order to understand the processes which cause these abrupt increases, changes in surface and groundwater were investigated. It is shown that salinity increases can be attributed to highly discrete groundwater discharge directly into the river from below. Hourly electrical conductivity data measured in the river showed regular, diurnal electrical conductivity fluctuations of up to 350 µS cm-1. These fluctuations could not be attributed to barometric pressure, temperature, or evapotranspiration. Instead, a similar periodicity in surface water electrical conductivity and groundwater height in nearby groundwater wells was found. Fluctuations were of similar periodicity to the orthotides which cause fluctuations in surface water height and are induced by Earth tides. The geology in the mid-catchment area indicates conditions are optimal for Earth tides to impact groundwater. The reporting of orthotidal changes in water chemistry in this article is believed to be the first of its kind in the scientific literature, with the large fluctuations noted having important implications for water monitoring and management in the catchment. Further research investigating Earth-tide-induced phases of groundwater heights will better constrain the relationships between surface water chemistry and groundwater height.

Outcomes following laparoscopic rectal cancer resection by supervised trainees.

BACKGROUND: The aim was to evaluate the applicability of laparoscopic surgery in the treatment of primary rectal cancer in a training unit. METHODS: A cohort analysis was undertaken of consecutive patients undergoing elective surgery for primary rectal cancer over a 7-year interval. Data on patient and operative details, and short-term clinicopathological outcomes were collected prospectively and analysed on an intention-to-treat basis. RESULTS: A total of 306 patients (213 men, 69·6 per cent) of median (i.q.r.) age 67 (58-73) years with a median body mass index of 26·6 (23·9-29·9) kg/m(2) underwent surgery. Median tumour height was 8 (6-11) cm from the anal verge, and 46 patients (15·0 per cent) received neoadjuvant radiotherapy. Seven patients (2·3 per cent) were considered unsuitable for laparoscopic surgery and underwent open resection; 299 patients (97·7 per cent) were suitable for laparoscopic surgery, but eight were randomized to open surgery as part of an ongoing trial. Some 291 patients (95·1 per cent) underwent a laparoscopic procedure, with conversion required in 29 (10·0 per cent). Surgery was partially or completely performed by trainees in 72·4 per cent of National Health Service patients (184 of 254), whereas private patients underwent surgery primarily by consultants. Median postoperative length of stay for all patients was 6 days and the positive circumferential resection margin rate was 4·9 per cent (15 of 306). CONCLUSION: Supervised trainees can perform routine laparoscopic rectal cancer resection.

Monolithically integrated tunable mode-locked laser diode source with individual pulse selection and post-amplification.

We report the generation of high-peak-power picosecond optical pulses in the 1.55 µm spectral band from a monolithically mode-locked laser integrated with a pulse selector and power booster. High-peak-power (>1 W) pulses with durations of 15.4 ps at a 55 MHz selected rate are demonstrated, indicating that this device shows promise as a high-peak-power pulsed light source for bio-photonic applications.

High speed OFDM-CDMA optical access network.

We demonstrate the feasibility of a 16 × 3.75 Gb/s (60 Gb/s aggregate) Orthogonal frequency division multiplexing-code division multiple access passive optical network for next-generation access applications. 3.75 Gb/s PON channel transmission over 25 km single-mode fiber shows 0.1 dB dispersion and 0.9 dB crosstalk penalties. Advantages of the system include high capacity, enhanced spectral efficiency, coding gain, and networking functions such as increased security and single-wavelength operation.

First demonstration of OFDM ECDMA for low cost optical access networks.

We demonstrate for the first time to the best of our knowledge an analogue orthogonal frequency division multiplexing (OFDM) based electrical code division multiplexing access (ECDMA) passive optical network (PON) for next generation access applications. Advantages of the system include low cost, high capacity, and enhanced spectral efficiency. A proof-of-principle 16 QAM OFDM ECDMA PON downlink experiment is used to show the transmission of an aggregate data rate of 24.8 Gb/s within an eight-user system. Transmission is achieved over 25 km of single-mode telecommunications fiber (SMF) with negligible dispersion and crosstalk penalties.

Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study.

PURPOSE: Esophageal cancer has a high mortality rate, and its multimodality treatment is often associated with significant rates of severe toxicity. Effort is needed to uncover ways to maximize effectiveness of therapy through identification of predictive markers of response and toxicity. As such, the aim of this study was to identify genes predictive of chemoradiotherapy-induced gastrointestinal toxicity using an immune pathway-targeted approach. METHODS: Adults with esophageal cancer treated with chemotherapy consisting of 5-fluorouracil and cisplatin and 45-50 Gy radiation were recruited to the study. Pre-therapy-collected whole blood was analyzed for relative expression of immune genes using real-time polymerase chain reaction (RT-PCR). Gene expression was compared between patients who experienced severe regimen-related gastrointestinal toxicity vs. those experiencing mild to moderate toxicity. RESULTS: Blood from 31 patients were analyzed by RT-PCR. Out of 84 immune genes investigated, TNF was significantly elevated (2.05-fold, p = 0.025) in the toxic group (n = 12) compared to the non-toxic group (n = 19). Nausea and vomiting was the most commonly documented severe toxicity. No associations between toxicity and response, age, sex, histology, or treatment were evident. CONCLUSIONS: This study supports evidence of TNF as a predictive biomarker in regimen-related gastrointestinal toxicity. Confirming these findings in a larger cohort is warranted.