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The objective was to evaluate the association between serum carotenoid levels and respiratory morbidity and mortality in a nationally representative sample of US adults. We assessed the association of serum carotenoid levels with respiratory morbidity and mortality using logistic regression and proportional hazards regression models. Meanwhile, a series of confounders were controlled in regression models and restricted cubic spline, which included age, sex, race, marriage, education, income, drinking, smoking, regular exercise, BMI, daily energy intake, vitamin E, vitamin C, fruit intake, vegetable intake, diabetes, hypertension, asthma, emphysema and chronic bronchitis. Compared with participants in the lowest tertiles, participants in the highest tertiles of serum total carotenoids, β -cryptoxanthin and lutein/zeaxanthin levels had a significantly lower prevalence of emphysema (OR total carotenoids = 0·61, 95% CI: 0·41-0·89, OR β -cryptoxanthin = 0·67, 95% CI: 0·49-0·92), chronic bronchitis (OR β -cryptoxanthin = 0·66, 95% CI: 0·50-0·87) and asthma (Q2: OR lutein/zeaxanthin = 0·78, 95% CI: 0·62-0·97); participants in the highest tertiles of total carotenoids, α -carotene, lutein/zeaxanthin and lycopene had a lower risk of respiratory mortality (hazard ratio (HR) total carotenoids = 0·62, 95% CI: 0·42-0·90, HR α -carotene = 0·54, 95% CI: 0·36-0·82, HR lutein/zeaxanthin = 0·48, 95% CI: 0·33-0·71, HR lycopene = 0·66, 95% CI: 0·45-0·96) than those in the lowest tertiles. Higher serum total carotenoids and β -cryptoxanthin levels is associated with decreased prevalence of emphysema and chronic bronchitis, and higher serum total carotenoids, α -carotene, lutein/zeaxanthin and lycopene levels had a lower mortality of respiratory disease.

Background and Objectives: Elevated troponin T (cTnT) values are associated with comorbidities and early mortality, in both cardiovascular and noncardiovascular diseases. The objective of this study is to evaluate the prognostic accuracy of the sole utilization of prehospital point-of-care cardiac troponin T to identify the risk of early in-hospital deterioration, including mortality within 28 days., Methods: We conducted a prospective, multicentric, controlled, ambulance-based, observational study in adults with acute diseases transferred with high priority by ambulance to emergency departments, between 1 January and 30 September 2020. Patients with hospital diagnosis of acute coronary syndrome were excluded. The discriminative power of the predictive cTnT was assessed through a discrimination model trained using a derivation cohort and evaluated by the area under the curve of the receiver operating characteristic on a validation cohort., Results: A total of 848 patients were included in our study. The median age was 68 years (25th-75th percentiles: 50-81 years), and 385 (45.4%) were women. The mortality rate within 28 days was 12.4% (156 cases). The predictive ability of cTnT to predict mortality presented an area under the curve of 0.903 (95% CI: 0.85-0.954; P < .001). Risk stratification was performed, resulting in three categories with the following optimal cTnT cut-off points: high risk greater than or equal to 100, intermediate risk 40-100 and low risk less than 40 ng/L. In the high-risk group, the mortality rate was 61.7%, and on the contrary, the low-risk group presented a mortality of 2.3%., Conclusions: The implementation of a routine determination of cTnT on the ambulance in patients transferred with high priority to the emergency department can help to stratify the risk of these patients and to detect unknown early clinical deterioration., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Three human protoparvoviruses, bufavirus (BuV), tusavirus (TuV) and cutavirus (CuV), have recently been discovered in diarrheal stool. BuV has been associated with diarrhea and CuV with cutaneous T-cell lymphoma, but there are hardly any data for TuV or CuV in stool or respiratory samples. Hence, using qPCR and IgG enzyme immunoassays, we analyzed 1072 stool, 316 respiratory and 445 serum or plasma samples from 1098 patients with and without gastroenteritis (GE) or respiratory-tract infections (RTI) from Finland, Latvia and Malawi. The overall CuV-DNA prevalences in stool samples ranged between 0-6.1% among our six patient cohorts. In Finland, CuV DNA was significantly more prevalent in GE patients above rather than below 60 years of age (5.1% vs 0.2%). CuV DNA was more prevalent in stools among Latvian and Malawian children compared with Finnish children. In 10/11 CuV DNA-positive adults and 4/6 CuV DNA-positive children with GE, no known causal pathogens were detected. Interestingly, for the first time, CuV DNA was observed in two nasopharyngeal aspirates from children with RTI and the rare TuV in diarrheal stools of two adults. Our results provide new insights on the occurrence of human protoparvoviruses in GE and RTI in different countries.

Background: Emergency medical services (EMS) routinely face complex scenarios where decisions should be taken with limited clinical information. The development of fast, reliable and easy to perform warning biomarkers could help in such decision-making processes. The present study aims at characterizing the validity of point-of-care lactate (pLA) during prehospital tasks for predicting in-hospital mortality within two days after the EMS assistance., Materials and Methods: Prospective, multicentric, ambulance-based and controlled observational study without intervention, including six advanced life support and five hospitals. The pLA levels were recorded during EMS assistance of adult patients. The validity of pLA to determine the in-hospital mortality was assessed by the area under the curve (AUC) of the receiver operating curve (ROC)., Results: A total of 2997 patients were considered in the study, with a median of 69 years (IQR 54-81) and 41.4% of women. The median pLA value was 2.7 mmol/L (1.9-3.8) in survivors and 5.7 mmol/L (4.4-7.6) in nonsurvivors. The global discrimination level of pLA reached an AUC of 0.867, being 1.9 mmol/L and 4 mmol/L the cut-off point for low and high mortality. The discrimination value of pLA was not affected by sex, age or pathology., Conclusions: Our results highlight the clinical importance of prehospital pLA to determine the in-hospital risk of mortality. The incorporation of pLA into the EMS protocols could improve the early identification of risky patients, leading to a better care of such patients., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: More than 60 years since the discovery of the respiratory syncytial virus (RSV), the effects of prenatal exposure to this virus remain largely unknown. In this investigation, we sought to find evidence of RSV seroconversion in cord blood and explore its clinical implications for the newborn., Methods: Offspring from 22 pregnant women with a history of viral respiratory infection during the third trimester of pregnancy (respiratory viral illness [RVI] group) and 40 controls were enrolled in this study between 1 September 2016 and 31 March 2019. Cord blood sera were tested for anti-RSV antibodies by indirect fluorescent antibody assay. RSV seropositivity was defined as the presence of anti-RSV immunoglobulin M (IgM) or immunoglobulin A (IgA), in addition to IgG in cord blood serum at ≥1:20 dilution., Results: Anti-RSV IgG was present in all cord blood serum samples from infants born to RVI mothers (95% confidence interval [CI] = 82%-100%), with 16 samples also having elevated titers for either anti-RSV IgA or IgM (73%; 95% CI = 52%-87%). No controls had evidence of anti-RSV antibodies. Eight (50%) seropositive newborns developed at least one respiratory tract finding, including respiratory distress syndrome (N = 8), respiratory failure (N = 3), and pneumonia (N = 1). RSV seropositive newborns also required more days on oxygen, had leukocytosis and elevated C-reactive protein (P = .025, P = .047, and P < .001, respectively)., Conclusion: This study provides evidence of acute seropositivity against RSV in cord blood of newborns delivered from mothers with a history of upper respiratory tract illness in the third trimester. Cord blood seropositivity for anti-RSV IgA or IgM was associated with adverse clinical and laboratory outcomes in newborns., (© 2020 Wiley Periodicals LLC.)

Objective: To assess whether increment of vitamin D daily intake results in improved serum25(OH) vitamin D levels and reduced respiratory morbidity in premature infants., Methods: A randomized double-blind clinical pilot trial, including preterm infants born at 32 + 6 to 36 + 6 weeks of gestation. The control group received 400 international units (IU) of cholecalciferol daily compared to 800 IU daily in the intervention group. Levels of 25(OH) vitamin D were measured at birth and 6 and 12 months of age. Respiratory morbidity was followed until 1 year of age., Results: Fifty subjects were recruited during the study period; the median measured 25(OH) vitamin D levels in the control vs intervention groups were: 26.5 vs 34 nmol/L (P = .271) at birth, 99 vs 75.5 nmol/L (P = .008) at 6 months and 72.5 vs 75 nmol/L (P = .95) at 12 months of age. Infants with insufficient vitamin D (<75 nmol/L) levels had higher respiratory morbidity. Serum vitamin 25(OH) D is a fair predictor for respiratory symptoms (area under the curve [AUC], 0.697; 95% confidence interval [CI], 0.509-0.885; P = .047) and for recorded acute respiratory illnesses (AUC, 0.745; 95% CI, 0.569-0.922; P = .012)., Conclusion: Doubling the daily intake of vitamin D in premature infants did not increase serum 25(OH) vitamin D level, due to poor compliance in the intervention group. We found an inverse association between serum 25(OH) vitamin D and respiratory symptoms, indicating vitamin D deficiency is a fair predictor for respiratory morbidity., (© 2020 Wiley Periodicals LLC.)

The COVID-19 pandemic goes along with increased mortality from acute respiratory disease. It has been suggested that vitamin D 3 supplementation might help to reduce respiratory disease mortality. We assessed the prevalence of vitamin D insufficiency and deficiency, defined by 25-hydroxyvitamin D (25(OH)D) blood levels of 30-50 and <30 nmol/L, respectively, and their association with mortality from respiratory diseases during 15 years of follow-up in a cohort of 9548 adults aged 50-75 years from Saarland, Germany. Vitamin D insufficiency and deficiency were common (44% and 15%, respectively). Compared to those with sufficient vitamin D status, participants with vitamin D insufficiency and deficiency had strongly increased respiratory mortality, with adjusted hazard ratios (95% confidence intervals) of 2.1 (1.3-3.2) and 3.0 (1.8-5.2) overall, 4.3 (1.3-14.4) and 8.5 (2.4-30.1) among women, and 1.9 (1.1-3.2) and 2.3 (1.1-4.4) among men. Overall, 41% (95% confidence interval: 20-58%) of respiratory disease mortality was statistically attributable to vitamin D insufficiency or deficiency. Vitamin D insufficiency and deficiency are common and account for a large proportion of respiratory disease mortality in older adults, supporting the hypothesis that vitamin D 3 supplementation could be helpful to limit the burden of the COVID-19 pandemic, particularly among women.

Long-term exposure to biomass-burning smoke (BS) is associated with chronic obstructive pulmonary disease (COPD), asthma, and other chronic inflammatory lung diseases. BS results from such processes as the burning of wood for indoor cooking and heating, with women and children having the highest exposure rate. This study aimed to analyze the accumulative alterations in cytokine levels associated with BS (from wood) compared to tobacco smoke (TS) in healthy adult women. The levels of 27 cytokines were analyzed in the serum of 100 women, including 40 tobacco smokers/non-exposed to BS (TS+/BS-), 30 never-smokers/exposed to BS (TS-/BS+) and 30 never-smokers/non-exposed to BS (TS-/BS-) as controls, using 27-Plex immunoassay. The chronic BS exposure index was rated at ≥100 h-years, and the tobacco-smoking index was ≥10 pack-years. Compared to TS-/BS-, TS+/BS- had higher levels of IL-2, IL-9, MCP-1, MIP-1β, and VEGF, while TS-/BS+ showed higher levels of IL-1ra, IL-6, IL-8, Eotaxin, IP-10, RANTES, and VEGF, presenting a distinct inflammatory profile that may favor an eosinophil-derived inflammatory response to BS exposure. Compared to TS+/BS-, TS-/BS+ expressed higher levels of IP-10 and IL-8, but lower levels of IL-2 and MIP-1β. Gene-disease database analysis showed that altered cytokines in both TS+/BS- and TS-/BS+ are associated with asthma, COPD, lung fibrosis, and lung cancer. In conclusion, chronic BS exposure induces distinct systemic inflammatory cytokine alterations compared to tobacco smokers in healthy women. These findings provide new insights into how long-term exposure to BS affects the inflammatory response-and potentially the health-of adult women., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Most diseases might be associated with acute or chronic inflammation, and the role of vitamin D in diseases has been extensively explored in recent years. Thus, we examined the associations of one of the best markers for inflammation - C-reactive protein (CRP) with 25-hydroxyvitamin D [25(OH)D] in 24 specific diseases. We performed cross-sectional analyses among 9,809 subjects aged ≥18 years who participated in the U.S. National Health and Nutrition Examination Survey (NHANES) in 2007~2010. The generalized additive model (GAM) was used to explore the associations of CRP with 25(OH)D in different diseases, adjusted for the age, gender, examination period and race. Distributions of CRP were significantly different (P < 0.05) in gender, examination period and race, and distributions of 25(OH)D were different (P < 0.05) in the examination period and race. Generally, CRP was negatively associated with 25(OH)D for majority diseases. 25(OH)D was negatively associated with CRP generally, and the associations were disease-specific and disease category-specific. In respiratory, gastrointestinal and mental diseases, the associations tended to be approximately linear. While in metabolic diseases, the associations were nonlinear, and the slope of the nonlinear curve decreased with 25(OH)D, especially when 25(OH)D < 30 μg/L.

Vitamin D deficiency is associated with higher all-cause mortality, but associations with specific causes of death are unclear. We investigated the association between circulating 25-hydroxyvitamin D (25(OH)D) concentration and cause-specific mortality using a case-cohort study within the Melbourne Collaborative Cohort Study (MCCS). Eligibility for the case-cohort study was restricted to participants with baseline dried blood spot samples and no pre-baseline diagnosis of cancer. These analyses included participants who died (n = 2307) during a mean follow-up of 14 years and a sex-stratified random sample of eligible cohort participants ('subcohort', n = 2923). Concentration of 25(OH)D was measured using liquid chromatography-tandem mass spectrometry. Cox regression, with Barlow weights and robust standard errors to account for the case-cohort design, was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for cause-specific mortality in relation to 25(OH)D concentration with adjustment for confounders. Circulating 25(OH)D concentration was inversely associated with risk of death due to cancer (HR per 25 nmol/L increment = 0.88, 95 % CI 0.78-0.99), particularly colorectal cancer (HR = 0.75, 95 % CI 0.57-0.99). Higher 25(OH)D concentrations were also associated with a lower risk of death due to diseases of the respiratory system (HR = 0.62, 95 % CI 0.43-0.88), particularly chronic obstructive pulmonary disease (HR = 0.53, 95 % CI 0.30-0.94), and diseases of the digestive system (HR = 0.44, 95 % CI 0.26-0.76). Estimates for diabetes mortality (HR = 0.64, 95 % CI 0.33-1.26) and cardiovascular disease mortality (HR = 0.90, 95 % CI 0.76-1.07) lacked precision. The findings suggest that vitamin D might be important for preventing death due to some cancers, respiratory diseases, and digestive diseases., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Bovine respiratory diseases (BRD) have long been considered a serious problem that causes major economic losses in feedlot calves (FC). This study aimed to determine the diagnostic and prognostic effect of selected biological markers including, procalcitonin (PCT), neopterin (NP), proinflammatory cytokines (IL-1β, IL-8, TNF-α, IF-γ), haptoglobin (HP) and serum amyloid A (SAA) on FC with BRD under field conditions. Sixty-nine FC that were identified to be infected with Mannheimia haemolytica and Histophilus somni and had different clinical respiratory signs (diseased group) were selected for this study. In addition, 20 healthy FC have been selected as a control group. We have detected higher serum levels of PCT, NP, HP, SAA, IL-1β, IL-8, TNF-α and IF-γ in diseased FC group compared with the control group. All tested markers revealed a high level of discrimination between BRD infected FC and healthy ones (AUC > 0.90). Moreover, the obtained data showed a high degree of prognostic accuracy for PCT, NP, IL-8, HP, IF-γ and IL-1β in predicting treatment response of FC with BRD at the selected thresholds (AUC = 0.99, 0.99, 0.97, 0.93, 0.88 and 0.82, respectively). Significant inhibition was observed for the selected biochemical markers in treated FC 7 days post-treatment. In conclusion, this study showed that BRD in FC was associated with significant alterations in serum APPs, proinflammatory cytokines, PCT and NPT levels. Furthermore, it demonstrated that these serum biomarkers are much higher in FC with BRD compared to recovered ones. Our data suggest that the measurement of PCT, NPT, APPs and cytokines together with the clinical examination may be a useful diagnostic and prognostic tool for assessment of FC naturally infected with M. haemolytica and H. somni., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Bovine respiratory disease (BRD) is a multifactorial disease complex and the leading infectious disease in post-weaned beef cattle. Clinical manifestations of BRD are recognized in beef calves within a high-risk setting, commonly associated with weaning, shipping, and novel feeding and housing environments. However, the understanding of complex host immune interactions and genomic mechanisms involved in BRD susceptibility remain elusive. Utilizing high-throughput RNA-sequencing, we contrasted the at-arrival blood transcriptomes of 6 beef cattle that ultimately developed BRD against 5 beef cattle that remained healthy within the same herd, differentiating BRD diagnosis from production metadata and treatment records. We identified 135 differentially expressed genes (DEGs) using the differential gene expression tools edgeR and DESeq2. Thirty-six of the DEGs shared between these two analysis platforms were prioritized for investigation of their relevance to infectious disease resistance using WebGestalt, STRING, and Reactome. Biological processes related to inflammatory response, immunological defense, lipoxin metabolism, and macrophage function were identified. Production of specialized pro-resolvin mediators (SPMs) and endogenous metabolism of angiotensinogen were increased in animals that resisted BRD. Protein-protein interaction modeling of gene products with significantly higher expression in cattle that naturally acquire BRD identified molecular processes involving microbial killing. Accordingly, identification of DEGs in whole blood at arrival revealed a clear distinction between calves that went on to develop BRD and those that resisted BRD. These results provide novel insight into host immune factors that are present at the time of arrival that confer protection from BRD., Competing Interests: The authors have declared that no competing interests exist.

Current diagnosis methods for Bovine Respiratory Disease (BRD) in feedlots have a low diagnostic accuracy. The current study aimed to search for blood biomarkers of BRD using 1 H NMR metabolomics and determine their accuracy in diagnosing BRD. Animals with visual signs of BRD (n = 149) and visually healthy (non-BRD; n = 148) were sampled for blood metabolomics analysis. Lung lesions indicative of BRD were scored at slaughter. Non-targeted 1 H NMR metabolomics was used to develop predictive algorithms for disease classification using classification and regression trees. In the absence of a gold standard for BRD diagnosis, six reference diagnosis methods were used to define an animal as BRD or non-BRD. Sensitivity (Se) and specificity (Sp) were used to estimate diagnostic accuracy (Acc). Blood metabolomics demonstrated a high accuracy at diagnosing BRD when using visual signs of BRD (Acc = 0.85), however was less accurate at diagnosing BRD using rectal temperature (Acc = 0.65), lung auscultation score (Acc = 0.61) and lung lesions at slaughter as reference diagnosis methods (Acc = 0.71). Phenylalanine, lactate, hydroxybutyrate, tyrosine, citrate and leucine were identified as metabolites of importance in classifying animals as BRD or non-BRD. The blood metabolome classified BRD and non-BRD animals with high accuracy and shows potential for use as a BRD diagnosis tool.

Elevated IgG4 concentrations in serum have received a great deal of attention recently, whereas the significance of decreased IgG4 levels was frequently neglected in spite of its close relation with infectious and noninfectious inflammations. In this review, based on the structural and functional characteristics of IgG4, we bring together case reports and research related to low levels of IgG4 and try to scratch the importance of decreased IgG4 concentrations in serum. As with elevated IgG4 levels, low serum IgG4-related diseases can be involved in multiple systems such as infection in the respiratory system, stroke in the circulatory system, and glomerulonephritis in the urinary system. Both genetic and immune dysregulation can contribute to decreased IgG4 levels. In the light of animal experiments, we believe that the mystery of low IgG4 can be revealed as long as enough attention is acquired., (© 2019 S. Karger AG, Basel.)

Background/objectives: Cancerous and non-cancerous respiratory diseases are common and contribute significantly to global disease burden. We aim to quantify the association between plasma vitamin C concentrations as an indicator of high fruit and vegetable consumption and the risk of incident respiratory diseases and associated mortality in a general population., Subjects/methods: Nineteen thousand three hundred and fifty-seven men and women aged 40-79 years without prevalent respiratory diseases at the baseline (1993-1997) and participating in the European Prospective Investigation into Cancer (EPIC)-Norfolk study in the United Kingdom were followed through March 2015 for both incidence and mortality from respiratory diseases., Results: There were a total of 3914 incident events and 407 deaths due to any respiratory diseases (excluding lung cancers), 367 incident lung cancers and 280 lung cancer deaths during the follow-up (total person-years >300,000 years). Cox's proportional hazards models showed that persons in the top quartiles of baseline plasma vitamin C concentrations had a 43% lower risk of lung cancer (hazard ratio (HR) 0.57; 95% confidence interval (CI): 0.41-0.81) than did those in the bottom quartile, independently of potential confounders. The results are similar for any non-cancerous respiratory diseases (HR 0.85; 0.77-0.95), including chronic respiratory diseases (HR 0.81; 0.69-0.96) and pneumonia (HR 0.70; 0.59-0.83). The corresponding values for mortality were 0.54 (0.35-0.81), 0.81 (0.59-1.12), 0.85 (0.44-1.66) and 0.61 (0.37-1.01), respectively. Confining analyses to non-smokers showed 42% and 53% risk reduction of non-smoking-related lung cancer incidence and death., Conclusions: Higher levels of vitamin C concentrations as a marker of high fruit and vegetable consumption reduces the risk of cancerous and non-cancerous respiratory illnesses including non-smoking-related cancer incidence and deaths.

Background: Prehospital Emergency Medical Services must attend to patients with complex physiopathological situations with little data and in the shortest possible time. The objective of this work was to study lactic acid values and their usefulness in the prehospital setting to help in clinical decision-making., Study Design: We conducted a longitudinal prospective, observational study on patients over 18 years of age who, after being evaluated by the Advanced Life Support Unit, were taken to the hospital between April and June 2018. We analyzed demographic variables, prehospital lactic acid values and early mortality (<30 days). The area under the curve of the receiver operating characteristic was calculated for the prehospital value of lactic acid., Results: A total of 279 patients were included in our study. The median age was 68 years (interquartile range: 54-80 years). Overall 30-day mortality was 9% (25 patients). The area under the curve for lactic acid to predict overall mortality at 30 days of care was 0.82 (95% CI: 0.76-0.89). The lactate value with the best sensitivity and specificity overall was 4.25 mmol/L with a sensitivity of 84% (95% CI: 65.3-93.6) and specificity of 70% (95% CI: 65.0-76.1)., Conclusions: The level of lactic acid can be a complementary tool in the field of prehospital emergencies that will guide us early in the detection of critical patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Measurement of nitric oxide (NO) levels in exhaled air from the upper and lower airways is currently used as a non-invasive marker of inflammation in respiratory diseases. Assessment of NO exhaled from the lower air respiratory tract is considered to be a quick method for confirmation and control of asthma in patients as well as an estimation of treatment efficiency. The main aim of this study was to determine differences between levels of exhaled nitric oxide (fractional exhaled NO; FeNO) in patients with respiratory disease as measured by an electrochemical analyzer. Measurements were taken in 352 pediatric patients aged 4-17 with cystic fibrosis (CF) (n = 43), asthma (n = 69), allergic rhinitis (AR) (n = 70), asthma and AR (n = 128) and non-diseased children (n = 42) recruited from the Allergology Outpatient Department, Provincial Hospital No 2, Rzeszów. The second objective of this study was to assess any correlations between FeNO and clinical parameters of patients. The level of FeNO in patients with CF was normal when compared with control subjects (10.8 ± 2.9 versus 11.4 ± 6 ppb). We found significantly higher FeNO in patients with asthma (26.6 ± 15.3 ppb, p < 0.001), AR (18.4 ± 9.6 ppb, p < 0.01) as well as in patients with both asthma and AR (43.3 ± 31.1 ppb, p < 0.001) when compared to healthy children. Statistical analysis revealed a positive correlation between FeNO and age, height and weight of control subjects, and height in children with AR. FeNO was independent of sex, BMI, spirometry and blood results as well as the type of residence in control children and subjects with CF, asthma, AR and combined asthma and AR. In conclusion, we found normal levels of FeNO in children with CF and elevated levels in patients with asthma, AR and combined asthma and AR as compared to control subjects. Due to conflicting data, there is still a need for additional research, especially related to regarding factors that affect FeNO levels in respiratory disease.

A clinically useful immune biomarker could potentially assist clinicians in their decision making. We stimulated T-cell proliferation to secret interferon gamma (IFN-γ) by phytohemagglutinin, and then measured the production of IFN-γ (mitogen value [M value]). We aimed to determine the relationship between the M value, clinical severity, and outcomes of diseases.In all, 484 patients admitted to intensive care units were enrolled in this retrospective study. The Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were collected within the first 24 hours. M value, C-reaction protein (CRP), procalcitonin (PCT), erythrocyte sedimentation rate (ESR), and routine blood tests were analyzed and collected during the study.When APACHE II scores were greater than 15 and M values were less than 6, the hospital mortality rose in a straight line. There was an inverse correlation between APACHE II score and M value (rs = -0.212, P < .001). There was a positive correlation between M value and lymphocyte numbers (b' = 0.249, P < .001); however, there was an inverse correlation between M value and WBC (b' = -0.230, P < .001), and ESR (b' = -0.100, P = .029). Neurological diseases had the greatest influence on APACHE II scores (b' = 10.356, P < .001), whereas respiratory diseases had the greatest influence on M value (b' = 1.933, P < .001). Furthermore, in the respiratory system, severe pneumonia had a greater influence on M value. Taking the APACHE II score as the gold standard, the area under the curve of M was 0.632 (95% confidence interval [CI] 0.575-0.690, P < .001), PCT was 0.647 (95% CI 0.589-0.705, P < .001), CRP was 0.570 (95% CI 0.511-0.629, P = .022), and ESR was 0.553 (95% CI 0.494-0.612, P = .078). Divided by M value = 5, the positive predictive value of the M value is 37.22% (115/309) and negative predictive value is 75.43% (132/175).The results show that the M values, PCT, and CRP were better than ESR to predict the severity of diseases. The number and proportion of lymphocytes also affected the result of the M value. To a certain extent, the M value may be a clinically useful immune biomarker, which may help clinicians objectively evaluate the severity of diseases, especially in the respiratory system.

Rationale: Although the health effects of beta carotene have been studied extensively, a systematic examination of serum concentrations and long-term mortality, including cardiovascular disease mortality, has not been reported., Objective: Explore whether serum beta carotene is associated with overall and cause-specific mortality and to elucidate the strength and dose-response of the association., Methods and Results: We conducted a prospective serological analysis of 29 103 men in the ATBC study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention). During 31 years of follow-up, 23 796 deaths occurred, including deaths because of cardiovascular disease (9869), cancer (7692), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2700). Serum beta carotene was assayed using high-performance liquid chromatography. Adjusting for major risk factors measured, men with higher serum beta carotene had significantly lower all-cause mortality (hazard ratios=0.81, 0.71, 0.69, and 0.64 for quintile 2 (Q2)-Q5 versus Q1, respectively; P trend <0.0001). Serum beta carotene was significantly associated with risk of death from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, diabetes mellitus, injuries and accidents, and other causes (Q5 versus Q1, hazard ratio=0.21-0.73, all P trend <0.0001). The all-cause mortality association was not materially impacted by adjustment for fruit and vegetable consumption (albeit, estimated with some measurement error) and was generally similar across subgroups of smoking intensity, alcohol consumption, trial supplementation, and duration of follow-up, but was significantly modified by age, years of smoking, and body mass index, with stronger inverse associations among men who were younger, smoked fewer years, and had a lower body mass index (all P interaction ≤0.0025)., Conclusions: This study provides evidence that higher beta carotene biochemical status is associated with lower overall, cardiovascular disease, heart disease, stroke, cancer, and other causes of mortality. The dose-response associations over a 30-year period were not attenuated by adjustment for other important risk factors and support greater fruit and vegetable consumption as a means to increase beta carotene status and promote longevity.

Objective: The purpose of this study was to evaluate potential relationships between cytokine gene expression, complete blood counts (CBC) and animals that were sick or would become sick. The CBC and the transcript abundance of cytokines and their receptors expressed in leukocytes were measured from calves at two early timepoints, and again after diagnosis with bovine respiratory disease (BRD)., Results: Blood was collected from calves at pre-conditioning (n = 796) and weaning (n = 791) for CBC. Blood counts were also measured for the calves with BRD (n = 13), and asymptomatic calves (n = 75) after weaning. The CBC were compared for these animals at 3 time points. At diagnosis, neutrophils were higher and basophils lower in sick animals (P < 0.05). To further characterize BRD responses, transcript abundance of 84 cytokine genes were evaluated in 5 calves with BRD and 9 asymptomatic animals at all time points. There was more data for CBC than transcript abundance; hence, animal and temporary environmental correlations between CBC and transcript abundance were exploited to improve the power of the transcript abundance data. Expression of CCL16, CXCR1, CCR1 was increased in BRD positive animals compared to controls (P-corrected < 0.1). Cytokine expression data may help to provide insight into an animal's health.

Purpose of Review: NSAIDs are the drugs most frequently involved in hypersensitivity reactions (HSR). These are frequently prescribed at all ages. HSR are of great concern and can affect people at any age. These drugs can induce reactions by stimulating the adaptive immune system (IgE or T cell), known as selective responders or more frequently by abnormalities in biochemical pathways related with prostaglandin metabolism. These are known as cross-intolerant. With some exceptions, skin testing and in-vitro studies are of little value in selective responders., Recent Findings: In the last years, several classifications have been provided based on clinical symptoms, time interval between drug intake and appearance of symptoms, response to other nonchemically related NSAIDs and the underlying disease. Based on this classification, several well differentiated categories within each group of entities cross-intolerant and selective responders are now recognized. The most complex groups for evaluation are cross-intolerant in which three major groups exist: NSAIDs exacerbated respiratory disease, NSAIDs exacerbated cutaneous disease and NSAIDs-induced urticaria/angioedema in the absence of chronic spontaneous urticaria. Within the selective responders, there are two mechanisms involved: drug-specific IgE or T-cell effector responses. New entities have been added to this classification like mixed reactions within the cross-intolerant category, that must manifest as anaphylaxis and multiple immediate selective reactions., Summary: The precise evaluation of patients with NSAIDs hypersensitivity following established guidelines will improve not only our understanding but also the management of these entities. As the number of patients affected with NSAIDs is important, further studies are warranted.

Background: Controversy exists as to the health effects of exposure to asphalt and crumb rubber modified (CRM) asphalt, which contains recycled rubber tyres., Objective: To assess exposures and effects on airway symptoms, lung function and inflammation biomarkers in conventional and CRM asphalt road pavers., Methods: 116 conventional asphalt workers, 51 CRM asphalt workers and 100 controls were investigated. A repeated-measures analysis included 31 workers paving with both types of asphalt. Exposure to dust, nitrosamines, benzothiazole and polycyclic aromatic hydrocarbon (PAH) was measured in worksites. Self-reported symptoms, spirometry test and blood sampling were conducted prework and postwork. Symptoms were further collected during off-season for asphalt paving., Results: Dust, PAHs and nitrosamine exposure was highly varied, without difference between conventional and CRM asphalt workers. Benzothiazole was higher in CRM asphalt workers (p<0.001). Higher proportions of asphalt workers than controls reported eye symptoms with onset in the current job. Decreased lung function from preworking to postworking was found in CRM asphalt workers and controls. Preworking interleukin-8 was higher in CRM asphalt workers than in the controls, followed by a decrement after 4 days of working. No differences in any studied effects were found between conventional and CRM asphalt paving., Conclusion: CRM asphalt workers are exposed to higher benzothiazole. Further studies are needed to identify the source of nitrosamines in conventional asphalt. Mild decrease in lung function in CRM asphalt workers and work-related eye symptoms in both asphalt workers were observed. However, our study did not find strong evidence for severe respiratory symptoms and inflammation response among asphalt workers., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The aim of the study was to assess serum C-reactive protein (CRP) level immediately after minimally invasive esophagectomy (MIE) as a surrogate of surgical invasiveness in patients who underwent esophagectomy., Methods: In total, 104 patients were enrolled in the study: 37 patients underwent MIE in the left lateral decubitus position (MIE-LP) and 67 patients underwent MIE in the prone position (MIE-PP). Serum CRP levels were assessed on POD 1, 3, 5, and 7 after MIE, and were compared with surgical outcomes and duration of systemic inflammatory response syndrome (SIRS) to investigate less invasiveness of the MIE., Results: Reduced serum CRP level on POD 1 was associated with PP during MIE (P < 0.001) and decreased blood loss (P = 0.03). MIE-PP was identified as a significant independent predictor of reduced CRP level on POD 1 (odds ratio 3.65, P = 0.042). CRP level on POD 7 was associated with gender (P = 0.02), position of MIE (P = 0.011), blood loss (P = 0.02), and respiratory complications and/or anastomotic leakage (P < 0.001). Postoperative respiratory and/or anastomotic complication was identified as a significant predictor of elevated serum CRP level on POD 7 (odds ratio 3.44, P = 0.048). Shorter duration of SIRS was shown in the patients with reduced serum CRP level on POD 1 and 7 (P = 0.03 and P < 0.001, respectively)., Conclusion: Serial assessments of serum CRP level immediately after MIE may be a possible indicator that can reflect surgical invasiveness and postoperative complications.

The objectives of this experiment were to determine the association of circulating cortisol, lactate, and glucose at, and prior to, weaning with ADG and incidences of bovine respiratory disease (BRD) in beef cattle. A blood sample was collected approximately 3 wk prior to weaning and at weaning from genetically diverse steers and heifers ( = 451). Cattle were weighed periodically throughout the study and ADG was calculated for the preweaning period (152 ± 15 d), the receiving period (45 d postweaning), the finishing period (200 d), and total postweaning ADG. Incidences of BRD were recorded and analyzed as a binary trait. Lung lesions were recorded at slaughter. Preweaning serum cortisol concentrations were positively associated ( = 0.040) with receiving ADG and explained 0.74% of the variance of receiving ADG. Preweaning glucose concentrations were positively associated ( < 0.001) with preweaning ADG and negatively associated with receiving ( = 0.003), finishing ( = 0.008), and total postweaning ADG ( = 0.002) and explained 2.0% of the variance in total postweaning ADG. Variation in preweaning serum glucose concentrations could be indicative of variation in milk consumption, and therefore indicate calves receiving less milk grow slower prior to weaning, but experience compensatory gain postweaning. Cattle that were diagnosed with BRD ( = 130) grew slower during the receiving phase ( = 0.004), but total postweaning ADG was not different from cattle not diagnosed with BRD ( = 0.683). Additionally, cattle that were diagnosed with BRD in the feedlot tended ( = 0.062) to have slightly lower preweaning serum glucose concentrations. Using a logistic regression analysis, none of the serum variables measured at or before weaning were predictive of developing BRD ( > 0.180). Weaning serum glucose concentrations tended to be predictive of the presence of lung lesions at weaning ( = 0.060). These data indicate that glucose measured early in life is associated with growth rate, and could indicate that carbohydrate metabolism could contribute to variation in ADG.

Introduction: Commercial air travel is usually without health incidents. However, there is a view that cabin environments may be detrimental to health, especially flights of 8 h or more. Concerns have been raised about deep vein thrombosis, upper respiratory tract infections, altitude sickness, and toxins from the engines., Methods: Passenger cabin simulators were used to achieve a comparative observational study with 8-h flights at pressures equivalent to terrestrial altitudes of ground, 4000, 6000, and 8000 ft. Biomarkers of thrombosis (D-Dimer), inflammation (interleukin-6), and respiratory dysfunction (FEV1) and oxygen saturation (Spo2) were measured, as well as pulse and blood pressure. The wellbeing of the passengers was also monitored., Results: During 36 flights, 1260 healthy subjects [626 women (F) and 634 men (M) (mean age = 43, SD = 16)] were assessed. Additionally, 72 subjects with chronic obstructive pulmonary disease (F = 32, M = 40, mean age = 48, SD = 17) and 74 with heart failure (F = 50, M = 24, mean age = 54, SD = 14) contributed to 11 flights. Additionally, 76 normal controls were observed while engaged in a usual day's work (F = 38, M = 38, mean age = 39, SD = 15). There were no health-significant changes in D-Dimer, interleukin-6, or FEV1. Spo2 varied as expected, with lowest values at 8000 ft and in patients with cardiopulmonary disease. The only differences from the controls were the loss of the normal diurnal variations in interleukin-6 and D-Dimer., Discussion: This very large, comparative, controlled study provides much reassurance for the traveling public, who use airline flights of up to 8 h. We did not show evidence of the development of venous thrombosis, inflammation, respiratory embarrassment, nor passenger distress. No significant symptoms or adverse effects were reported.Ideal Cabin Environment (ICE) Research Consortium of the European Community 6th Framework Programme. Health effects of airline cabin environments in simulated 8-hour flights. Aerosp Med Hum Perform. 2017; 88(7):651-656.

Aims: To evaluate the interest of brain natriuretic peptide (BNP) for heart failure (HF) diagnosis in very old patients., Methods and Results: A total of 383 patients aged 80 years or older, hospitalized in geriatrics care for dyspnoea, had a BNP measurement at the acute phase. Independent cardiologists blinded to BNP values classified the patients into cardiac vs. respiratory aetiology according to the European Society of Cardiology guidelines. Mean (SD) age was 88.5 (5.4) years, 66% (n = 254) of patients were women, 62% (n = 238) had cardiac dyspnoea and 38% (n = 145) had respiratory dyspnoea. The BNP levels were significantly higher in the cardiac group (median = 385.5 ng/L, interquartile range = 174.0-842.0) than in the respiratory group (median = 172.0 ng/L, interquartile range = 70.8-428.0; P < 0.001). On its own, BNP showed poor discriminative ability [area under the curve (AUC) = 0.68; 95% confidence interval (CI) 0.62-0.73] for the diagnostic. In multivariate analysis, BNP remained independently associated with the cardiac aetiology after full-adjustment (odds ratio 1 log increase = 1.87; 95% CI 1.28-2.74), but did not improve the discrimination between the cardiac and the respiratory aetiologies (ΔAUC = 0.013, P = 0.16). In addition, although adding BNP to the other predictive covariates yielded a significant continuous NRI of 57.8% (95% CI 31.2-83.5%), the mean changes in individual predicted probabilities were too low (<3%) to be clinically relevant., Conclusion: In this population of very old patients with acute dyspnoea, despite being independently associated with the cardiac aetiology, BNP was not useful for better discriminating cardiac vs. respiratory origin., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: Postoperative complications are associated with poor cancer-specific survival in various types of cancer surgery. Recent studies suggest that systemic inflammation induced by surgical trauma can accelerate the adhesion of circulating tumor cells to the vascular endothelium of distant organs, resulting in early cancer recurrence. We investigated the impact of postoperative cardiopulmonary complications on cancer recurrence following lung cancer surgery., Methods: From a prospective database of 675 consecutive patients who underwent curative surgery for lung cancer between 2007 and 2012, the incidence of postoperative cardiopulmonary complications, white blood cell counts, and C-reactive protein levels were evaluated in the acute phase after surgery. Four patients had both cardiovascular and respiratory complications. The remaining 671 patients were divided into 3 groups: patients without cardiopulmonary complications; those with cardiovascular complications; and those with respiratory complications. The incidence of cancer recurrence was compared among the three groups., Results: Postoperative cardiovascular or respiratory complications were identified in 94 (14%) or 25 (4%) patients, respectively. Postoperative white blood cell counts and C-reactive protein levels were significantly higher in those with postoperative respiratory complications than in those without. There was a significantly higher incidence of cancer recurrence in those with postoperative respiratory complications than in those without (48.0 vs. 16.8%; p < 0.0001). Multiple regression analysis adjusted for age, sex, and pathological staging showed that the incidence of postoperative respiratory complications was a significant predictor of cancer recurrence., Conclusions: The presence of respiratory complications following lung cancer surgery was a significant predictor of cancer recurrence.

In human respiratory disease studies, liquid samples such as nasal secretion (NS), lung epithelial lining fluid (ELF), or upper airway mucosal lining fluid (MLF) are frequently collected, but their volumes often remain unknown. The lack of volume information makes it hard to estimate the actual concentration of recovered active pharmaceutical ingredient or biomarkers. Urea has been proposed to serve as a sample volume marker because it can freely diffuse through most body compartments and is less affected by disease states. Here, we report an easy and reliable LC-MS/MS method for cross-matrix measurement of urea in serum, plasma, universal transfer medium (UTM), synthetic absorptive matrix elution buffer 1 (SAMe1) and synthetic absorptive matrix elution buffer 2 (SAMe2) which are commonly sampled in human respiratory disease studies. The method uses two stable-isotope-labeled urea isotopologues, [ 15 N 2 ]-urea and [ 13 C, 15 N 2 ]-urea, as the surrogate analyte and the internal standard, respectively. This approach provides the best measurement consistency across different matrices. The analyte extraction was individually optimized in each matrix. Specifically in UTM, SAMe1 and SAMe2, the unique salting-out assisted liquid-liquid extraction (SALLE) not only dramatically reduces the matrix interferences but also improves the assay recovery. The use of an HILIC column largely increases the analyte retention. The typical run time is 3.6min which allows for high throughput analysis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Procalcitonin (PCT), a precursor protein of the hormone calcitonin, is a sensitive inflammatory marker in human medicine, which is primarily used for diagnosis of bacterial sepsis, but is also useful in diagnosis of exacerbation of asthma and COPD. In this study, PCT was evaluated as a potential biomarker for different chronic pneumopathies in the horse using an equine specific ELISA in comparison to established clinical markers and different interleukins. Sixty-four horses were classified as free of respiratory disease, recurrent airway obstruction (RAO), inflammatory airway disease (IAD) or chronic interstitial pneumopathy (CIP) using a scoring system. PCT concentrations were measured in plasma (n = 17) and in the cell-free supernatant of bronchoalveolar lavage (n = 64). PCT concentrations were correlated to interleukins IL-1ß and IL-6 in BALF, clinical findings and BALF cytology., Results: The median PCT concentrations in plasma were increased in respiratory disease (174.46 ng/ml, n = 7) compared to controls (13.94 ng/ml, n = 10, P = 0.05) and correlated to PCT in BALF supernatant (rs = 0.48). Compared to controls (5.49 ng/ml, n = 15), median PCT concentrations in BALF supernatant correlated to the overall clinical score (rs = 0.32, P = 0.007) and were significantly increased in RAO (13.40 ng/ml, n = 21) and IAD (16.89 ng/ml, n = 16), while no differences were found for CIP (12.02 ng/ml, n = 12). No significant increases were found for IL-1 and IL-6 between controls and respiratory disease in general as well as different disease groups., Conclusions: Although some correlations were found between PCT in plasma, BALF supernatant and clinical scores, PCT in BALF does not seem to be a superior marker compared to established clinical markers. PCT in plasma seems to be more promising and a greater number of samples should be evaluated in further studies.

Background: High rates of upper and lower airways disease have occurred in Fire Department of the City of New York (FDNY) workers exposed to the World Trade Center (WTC) disaster site. Most experienced acute declines in pulmonary function, and some continued to experience decline over 14 years of follow-up. Similarly, some with rhinosinusitis had symptoms requiring sinus surgery., Aim: To increase generalizability of biomarker investigation, we describe biomarkers of risk for upper and lower airway injury that do not require stored serum., Methods: We review WTC biomarker literature., Results: Cytokines expressed in stored serum from the first 6 months post-9/11 can identify individuals at higher risk for future abnormal pulmonary function., Conclusion: This research will help identify individuals at high risk of lung and sinus disease that develop after these, or future, irritant exposures for intensive monitoring and treatment. It may also identify targets for effective therapeutic interventions. Am. J. Ind. Med. 59:788-794, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Outcome for patients experiencing out-hospital cardiac arrest (OHCA) due to respiratory causes is poor, even with treatment by therapeutic hypothermia (TH). The purpose of this study is to clarify difference in outcome and respiratory state during resuscitation between cases due to respiratory causes versus those due to cardiac causes, to establish alternative strategies for the patient. This study was conducted as a retrospective analysis of patients with post CA syndrome who underwent TH. Patients were divided into two groups according to cause of CA: cardiac (C group) or respiratory (R group). Utstein Style data, outcome, and arterial blood gas (ABG) findings after emergency room admission of the two groups were compared. Of 74 patients treated with TH during the 2-year study period, 49 were placed in the C group and 19 in the R group. The rates of ventricular fibrillation/pulseless ventricular tachycardia at initial rhythm were significantly higher in the C group than in the R group. The rate of favorable neurological outcome was significantly higher in the C group (15/49: 30.6%) than in the R group (1/19: 5.3%) 30 days after resuscitation. In the ABG findings, PaCO2 was significantly higher in the R group than in the C group. For patients experiencing OHCA from respiratory causes, TH was less effective and PaCO2 accumulated immediately after admission. From this, interpretation of the significance of PaCO2 in these patients at the early stage after return of spontaneous circulation should be seriously considered.

In spite of long-standing interest of researchers to problem of high susceptibility of frequently ill children to agents of respiratory diseases, so far no pathogenic mechanisms of this phenomenon were established. Therefore, selection of appropriate techniques of prevention of frequent respiratory diseases is complicated. Previously, the key role of cortisol and lipid-transferring system of blood in pathologic process was demonstrated. However, the assumption was expressed concerning heterogeneity of group of frequently ill children in content of cortisol - possibly conditioned by polymorphism of receptors to cortisol and as a sequence alteration of their quantity and sensitivity to this hormone. In turn, occurring imbalance between amount of cortisol and receptors is able to result in large specter of metabolic and immunological alterations. The purpose of this study was investigation of content of cortisol in blood, amount of its nuclear receptors in leukocytes and also lipid-transferring system of blood of frequently ill children examined in autumn in inter-morbid period. The statistical analysis of received results permits stating that group of frequently ill children is heterogeneous and is presented by two sub-groups with reliably differing by level of cortisol and ratio cortisol/ receptors to cortisol. This phenomenon cab be conditioned by polymorphism of genes coding nuclear receptors to cortisol, ATP- binding cassette transporter, lecithin cholesterol acyltransferase, scavenger-receptors. The step-by-step discriminant analysis with development of discriminant diagnostic model detected cortisol, cholesterol of high density lipoproteins and cholesterol of low density lipoproteins as valuable factors being active participants of development ofphenomenon of frequently ill children.

Objectives: Modern management of myeloma has significantly improved survival, with increasing numbers of patients living beyond a decade. However, little is known about the long-term cardiovascular and respiratory status of intensively treated and multiply relapsed survivors., Methods: We performed detailed cardiovascular and respiratory evaluations in patients with intensively treated, advanced but stable myeloma. All patients had received at least two lines of treatment, including at least one haematopoietic stem cell transplantation procedure, but had stable, controlled disease and were off active treatment at the time of evaluation., Results: Thirty-two patients with a median duration of 6 years (range 2-12) from original diagnosis of myeloma and three lines (range 2-6) of treatment were evaluated. Despite normal physical examination in the majority, there was a high prevalence of sub-clinical cardiac and respiratory dysfunction, reflected by abnormalities of electrocardiography (45%), echocardiography (50%), serum N-terminal pro-B-type natriuretic peptide level (NT-pro-BNP, 50%), and pulmonary function testing (45%). NT-pro-BNP level correlated negatively with quality of life (P = 0.012) and positively with serum ferritin (P = 0.027). Dyspnoea score correlated with BMI (P = 0.001). Risk factors for cardiovascular disease (obesity, hypertension, hyperlipidaemia, and hyperinsulinaemia) were common., Discussion: Even in the absence of overt clinical features, the majority of intensively treated long-term survivors of myeloma have established cardiovascular and/or respiratory dysfunction, above levels expected in the general population of a similar age., Conclusion: This study supports routine screening and lifestyle modification combined with primary and secondary preventive strategies to reduce cardiovascular and respiratory disease and to preserve quality of life in transplanted myeloma patients.

Acute phase proteins are sensitive markers of inflammation, which are highly conserved across taxa. Although the utility of these proteins are becoming well defined in human and domestic animal medical fields, their role in nondomestic species remains unclear. In this communication, a 20-yr-old Przewalski's horse was presented for unresolving aspiration pneumonia, which cultured a unique Actinomyces-like bacteria. Despite waxing and waning clinical signs and minimal changes on baseline hematologic analysis, protein electrophoresis, serum amyloid A, and surfactant protein D serum concentrations showed changes that more accurately reflected the clinical severity of this case.

Objective: To evaluate the effect of preconsultation C reactive protein (CRP) screening on antibiotic prescribing and referral to hospital in Norwegian primary care settings with low prevalence of serious infections., Design: Randomised controlled observational study at out-of-hours services in Norway., Setting: Primary care., Participants: 401 children (0-6 years) with fever and/or respiratory symptoms were recruited from 5 different out-of-hours services (including 1 paediatric emergency clinic) in 2013-2015., Intervention: Data were collected from questionnaires and clinical examination results. Every third child was randomised to a CRP test before the consultation; for the rest, the doctor ordered a CRP test if considered necessary., Outcome Measures: Main outcome variables were prescription of antibiotics and referral to hospital., Results: In the group pretested with CRP, the antibiotic prescription rate was 26%, compared with 22% in the control group. In the group pretested with CRP, 5% were admitted to hospital, compared with 9% in the control group. These differences were not statistically significant. The main predictors for ordering a CRP test were parents' assessment of seriousness of the illness and the child's temperature. Paediatricians ordered CRP tests less frequently than did other doctors (9% vs 56%, p<0.001)., Conclusions: Preconsultation screening with CRP of children presenting to out-of-hours services with fever and/or respiratory symptoms does not significantly affect the prescription of antibiotics or referral to hospital., Trial Registration Number: NCT02496559; Results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background/aims: Patients with liver cirrhosis (LC) are at risk for critical events leading to Intensive Care Unit (ICU) admission. Coagulopathy in cirrhotic patients is complex and can lead to bleeding as well as thrombosis. The aim of this study was to investigate bleeding complications in critically ill patients with LC admitted to a medical ICU (MICU)., Methods: All adult patients admitted to our MICU with a diagnosis of LC from January 2006 to December 2012 were retrospectively assessed. Patients with major bleeding at the time of MICU admission were excluded from the analysis., Results: A total of 205 patients were included in the analysis. The median patient age was 62 years, and 69.3% of the patients were male. The most common reason for MICU admission was acute respiratory failure (45.4%), followed by sepsis (27.3%). Major bleeding occurred in 25 patients (12.2%). The gastrointestinal tract was the most common site of bleeding (64%), followed by the respiratory tract (20%). In a multivariate analysis, a low platelet count at MICU admission (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97 to 0.99) and sepsis (OR, 8.35; 95% CI, 1.04 to 67.05) were independent risk factors for major bleeding. The ICU fatality rate was significantly greater among patients with major bleeding (84.0% vs. 58.9%, respectively; p = 0.015)., Conclusions: Major bleeding occurred in 12.2% of critically ill cirrhotic patients admitted to the MICU. A low platelet count at MICU admission and sepsis were associated with an increased risk of major bleeding during the MICU stay. Further study is needed to better understand hemostasis in critically ill patients with LC.

Background: Following the Chernobyl nuclear disaster of 1986, vast areas of Ukraine became contaminated with radionuclides. We examined health effects of school-based food intervention for children in a rural region Narodichi, Ukraine, exposed to low-level radiation through diet of locally produced foods. Until 1995, children received three daily meals with low content of artificial radionuclides which were subsequently reduced to two., Methods: Annual health screening data (1993-1998) were examined using a quasi-experimental regression discontinuity analysis (n = 947 children; 3,573 repeated measurements). Generalized Estimating Equation models evaluated effect of the food supplementation reduction on hematologic measures and prevalence of anemia, acute respiratory illnesses and diseases of immune system., Results: Prior improvement of several hematologic parameters diminished after food supplementation was reduced. From 1995 to 1996, levels of hemoglobin and erythrocytes decreased from 12.63 (95% CI: 12.56-12.71) to 12.46 g/dL (% CI: 12.39-12.52) and from 4.10 (95% CI: 4.07-4.12) to 4.02 (95% CI: 4.00-4.04) × 10(12)/L, respectively. In agreement, the prevalence ratio (PR) of previously declining anemia increased from 0.57 to 1.31 per year (p(interaction )< .0001). The relation between food supplementation and hemoglobin levels was modified by residential (137)Cs soil levels. After food supply reduction, PR of common cold and bronchitis increased from 1.27 to 2.32 per year (p(interaction) = 0.01) and from 1.09 to 1.24 per year (p(interaction) = 0.43), respectively., Conclusions: Food supplementation provided by the Ukrainian government likely prevented development of anemia in many of the children residing in the contaminated district. Food supplementation after the community exposure to radioactivity through a diet of locally grown foods should be considered as an effective approach to reduce adverse health effects of radiation.

Background: The identification of serum biomarkers of lung inflammation would facilitate the diagnosis of inflammatory airway disease (IAD) in horses., Hypothesis: Horses with IAD have higher serum concentrations of markers of inflammation compared to controls., Animals: Twelve horses with IAD and 10 control horses., Methods: This was a prospective case-control study. Blood and BALF were collected from horses with IAD and controls. Serum concentration of surfactant protein D (SP-D), haptoglobin, serum amyloid A (SAA) and of the soluble form of triggering receptor expressed on myeloid cells 1 (sTREM-1) was measured using commercial ELISA tests., Results: Horses with IAD had higher serum concentration (log-transformed values) of SP-D (mean ± SD: 1.773 ± 0.51), haptoglobin (6.657 ± 0.202) and SAA (0.128 ± 0.396) compared to controls (0.942 ± 0.226, 6.38 ± 0.22, -0.398 ± 0.319, respectively; P < .01 for all). Furthermore, the concentrations of SP-D and haptoglobin combined allowed differentiating the 2 groups (IAD: 8.43 ± 0.564, controls: 7.322 ± 0.249, P < .0001) with a sensitivity and specificity of 100% when a cut-off of 7.70 (log value) was employed., Conclusions and Clinical Importance: Surfactant protein D and haptoglobin serum concentrations could be a diagnostic aid in IAD. Further studies are necessary to establish the specificity of our findings before they can be applied in everyday practice., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.)

Background: The prevalence of allergic respiratory disease tends to increase in populations that adopt the so-called Westernized lifestyle. We investigated the association between atopy and several possible lifestyle-related factors in seven Danish population-based studies., Methods: A total of 20048 persons participated in the seven studies. We used logistic regression to analyse the associations between possible determinants and atopy defined as serum specific IgE or skin prick test positivity against inhalant allergens. Associations were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). In addition, individual participant data meta-analyses were performed., Results: Atopy was significantly associated with younger age (OR per 1 year increase in age: 0.97; 95% CI: 0.97, 0.98); male sex (OR for males versus females: 1.34; 95% CI: 1.24, 1.45), heavy drinking (OR for heavy drinkers versus light drinkers: 1.15; 95% CI: 1.04, 1.27), never smoking (OR for current versus never smokers: 0.73; 95% CI: 0.67, 0.80), and higher educational level (OR for educated versus uneducated: 1.27; 95% CI: 1.15, 1.41). Atopy was not associated with blood pressure, serum total cholesterol, physical activity or body mass except in women only, where we found a positive association (OR for obese vs. normal weight: 1.18; 95% CI: 1.00, 1.39) with ptrend = 0.032., Conclusions: Of interest for preventive purposes, we found that atopy was associated with some of the reversible lifestyle-related factors that characterize a Westernized lifestyle.

The biochemical study of activity of serum cholinesterase in workers of industrial enterprise was carried out on the example of petrochemical industry. The indicators of average activity of enzyme and prevalence of indicators going beyond limits of reference values were analyzed depending on manufacturing-labor experience, profession and diseases established in workers. The main diseases, professional and labor experience groups were identified where activity of cholinesterase significantly changes. The impact of labor experience and profession on level of activity ofenzyme in blood serum is demonstrated.

Background: Systemic inflammation is observed in horses with heaves and could also be present in horses with a lesser degree of pulmonary inflammation., Hypothesis/objectives: It was hypothesized that racehorses with inflammatory airway disease (IAD) have increased concentration of circulating acute phase proteins. The objective of this study was to compare serum acute phase proteins of racehorses with and without lower airway inflammation., Animals: Serum from 21 client-owned Standardbred racehorses with exercise intolerance and lower airway inflammation and serum from 10 client-owned Standardbred racehorses with exercise intolerance without lower airway inflammation., Methods: In a case-control study, serum samples from previously characterized horses presented for exercise intolerance with or without lower airway inflammation based on bronchoalveolar lavage fluid cytology were analyzed for serum amyloid A protein (SAA), C-reactive protein (CRP), and haptoglobin using commercial ELISAs., Results: There was no significant differences between groups for SAA (non-IAD versus IAD, median (range): 3.47 (0.06-34.94) versus 6.33 (0.06-80) μg/mL, P = .49), CRP (10.87 (2.05-29.03) versus 4.63 (0.02-31.81) μg/mL, P = .23) or haptoglobin (900.36 (607.99-2018.84) versus 749.54 (530.81-1076.95) μg/mL, P = .09)., Conclusions and Clinical Importance: In this population of poorly performing racehorses in training, serum SAA, CRP, and haptoglobin were not helpful in distinguishing between horses with IAD from horses with exercise intolerance from other causes., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Respiratory diseases are associated with pulmonary oxidative stress and inflammatory processes. Though studies in animal models suggest that dietary polyphenols improve lung injury, no intervention studies were carried out in humans. The aim of this study was to determine whether the intake of an anthocyanin-rich maqui extract improved H2O2 and IL-6 concentrations in exhaled breath condensates (EBCs) from asymptomatic smokers., Findings: 15 asymptomatic smokers with mild cigarette smoking (3 pack-year [2.4 - 7.7]) (mean [CI95%]) were recruited in this exploratory longitudinal study. They ingested 2 g of maqui extract (polyphenol content = 5.18 ± 2.00 g GAE/100 g; FRAP value = 27.1 ± 2.0 mmol Fe(++)/100 g), twice daily for two weeks. EBCs were collected before and after treatment and the changes in H2O2 and IL-6 concentrations were determined by fluorimetry and Elisa, respectively. The EBC contents of H2O2 and IL-6 H2O2 before and after treatment in smokers were also compared with those determined in single EBC samples from 8 healthy non-smokers subjects. At baseline, the H2O2 concentrations were higher and those of IL-6 lower in the smokers than in the non-smokers. Maqui extract significantly decreased H2O2 (p < 0.0002) and increased IL-6 (p < 0.004) in the EBC from smokers. The EBC concentrations of H2O2 and IL-6 after maqui administration did not differ between smokers and non-smokers., Conclusions: Maqui extract normalizes IL-6 and H2O2 concentrations in EBC from humans with mild smoking habits. If confirmed, these results suggest that dietary polyphenols might be considered as an interesting alternative for the dietary management of respiratory disorders.

Polymorbid patients, diverse diagnostic and therapeutic options, more complex hospital structures, financial incentives, benchmarking, as well as perceptional and societal changes put pressure on medical doctors, specifically if medical errors surface. This is particularly true for the emergency department setting, where patients face delayed or erroneous initial diagnostic or therapeutic measures and costly hospital stays due to sub-optimal triage. A "biomarker" is any laboratory tool with the potential better to detect and characterise diseases, to simplify complex clinical algorithms and to improve clinical problem solving in routine care. They must be embedded in clinical algorithms to complement and not replace basic medical skills. Unselected ordering of laboratory tests and shortcomings in test performance and interpretation contribute to diagnostic errors. Test results may be ambiguous with false positive or false negative results and generate unnecessary harm and costs. Laboratory tests should only be ordered, if results have clinical consequences. In studies, we must move beyond the observational reporting and meta-analysing of diagnostic accuracies for biomarkers. Instead, specific cut-off ranges should be proposed and intervention studies conducted to prove outcome relevant impacts on patient care. The focus of this review is to exemplify the appropriate use of selected laboratory tests in the emergency setting for which randomised-controlled intervention studies have proven clinical benefit. Herein, we focus on initial patient triage and allocation of treatment opportunities in patients with cardiorespiratory diseases in the emergency department. The following five biomarkers will be discussed: proadrenomedullin for prognostic triage assessment and site-of-care decisions, cardiac troponin for acute myocardial infarction, natriuretic peptides for acute heart failure, D-dimers for venous thromboembolism, C-reactive protein as a marker of inflammation, and procalcitonin for antibiotic stewardship in infections of the respiratory tract and sepsis. For these markers we provide an overview on physiopathology, historical evolution of evidence, strengths and limitations for a rational implementation into clinical algorithms. We critically discuss results from key intervention trials that led to their use in clinical routine and potential future indications. The rational for the use of all these biomarkers, first, tackle diagnostic ambiguity and consecutive defensive medicine, second, delayed and sub-optimal therapeutic decisions, and third, prognostic uncertainty with misguided triage and site-of-care decisions all contributing to the waste of our limited health care resources. A multifaceted approach for a more targeted management of medical patients from emergency admission to discharge including biomarkers, will translate into better resource use, shorter length of hospital stay, reduced overall costs, improved patients satisfaction and outcomes in terms of mortality and re-hospitalisation. Hopefully, the concepts outlined in this review will help the reader to improve their diagnostic skills and become more parsimonious laboratory test requesters.

To explore associations of exposure to ambient and indoor air particulate and bio-aerosol pollutants with cardiovascular and respiratory disease markers, we utilized seven repeated measurements from 48 elderly subjects participating in a 4-week home air filtration study. Microvascular function (MVF), lung function, blood leukocyte counts, monocyte adhesion molecule expression, C-reactive protein, Clara cell protein (CC16) and surfactant protein-D (SPD) were examined in relation to exposure preceding each measurement. Exposure assessment included 48-h urban background monitoring of PM10, PM2.5 and particle number concentration (PNC), weekly measurements of PM2.5 in living- and bedroom, 24-h measurements of indoor PNC three times, and bio-aerosol components in settled dust on a 2-week basis. Statistically significant inverse associations included: MVF with outdoor PNC; granulocyte counts with PM2.5; CD31 expression with dust fungi; SPD with dust endotoxin. Significant positive associations included: MVF with dust bacteria; monocyte expression of CD11 with PM2.5 in the bedroom and dust bacteria and endotoxin, CD31 expression with dust serine protease; serum CC16 with dust NAGase. Multiple comparisons demand cautious interpretation of results, which suggest that outdoor PNC have adverse effects on MVF, and outdoor and indoor PM2.5 and bio-aerosols are associated with markers of inflammation and lung cell integrity.

Background: Despite epidemiological findings showing increased air pollution related cardiovascular diseases (CVD), the knowledge of the involved molecular mechanisms remains moderate or weak. Particulate matter (PM) produces a local strong inflammatory reaction in the pulmonary environment but there is no final evidence that PM physically enters and deposits in blood vessels. Extracellular vesicles (EVs) and their miRNA cargo might be the ideal candidate to mediate the effects of PM, since they could be potentially produced by the respiratory system, reach the systemic circulation and lead to the development of cardiovascular effects.The SPHERE ("Susceptibility to Particle Health Effects, miRNAs and Exosomes") project was granted by ERC-2011-StG 282413, to examine possible molecular mechanisms underlying the effects of PM exposure in relation to health outcomes., Methods/design: The study population will include 2000 overweight (25 < BMI < 30 kg/cm2) or obese (BMI ≥ 30 kg/cm2) subjects presenting at the Center for Obesity and Work (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy).Each subject donates blood, urine and hair samples. Extensive epidemiological and clinical data are collected. Exposure to PM is assigned to each subject using both daily PM10 concentration series from air quality monitors and pollutant levels estimated by the FARM (Flexible air Quality Regional Model) modelling system and elaborated by the Regional Environmental Protection Agency.The recruitment period started in September 2010 and will continue until 2015. At December 31, 2013 we recruited 1250 subjects, of whom 87% lived in the province of Milan.Primary study outcomes include cardiometabolic and respiratory health effects. The main molecular mechanism we are investigating focuses on EV-associated microRNAs., Discussion: SPHERE is the first large study aimed to explore EVs as a novel potential mechanism of how air pollution exposure acts in a highly susceptible population. The rigorous study design, the availability of banked biological samples and the potential to integrate epidemiological, clinical and molecular data will also furnish a powerful base for investigating different complementary molecular mechanisms. Our findings, if confirmed, could lead to the identification of potentially reversible alterations that might be considered as possible targets for new diagnostic and therapeutic interventions.

Background: Vitamin D is associated with many health conditions, but optimal blood concentrations are still uncertain., Objectives: We examined the prospective relation between serum 25-hydroxyvitamin D [25(OH)D] concentrations [which comprised 25(OH)D3 and 25(OH)D2] and subsequent mortality by the cause and incident diseases in a prospective population study., Design: Serum vitamin D concentrations were measured in 14,641 men and women aged 42-82 y in 1997-2000 who were living in Norfolk, United Kingdom, and were followed up to 2012. Participants were categorized into 5 groups according to baseline serum concentrations of total 25(OH)D <30, 30 to <50, 50 to <70, 70 to <90, and ≥ 90 nmol/L., Results: The mean serum total 25(OH)D was 56.6 nmol/L, which consisted predominantly of 25(OH)D3 (mean: 56.2 nmol/L; 99% of total). The age-, sex-, and month-adjusted HRs (95% CIs) for all-cause mortality (2776 deaths) for men and women by increasing vitamin D category were 1, 0.84 (0.74, 0.94), 0.72 (0.63, 0.81), 0.71 (0.62, 0.82), and 0.66 (0.55, 0.79) (P-trend < 0.0001). When analyzed as a continuous variable and with additional adjustment for body mass index, smoking, social class, education, physical activity, alcohol intake, plasma vitamin C, history of cardiovascular disease, diabetes, or cancer, HRs for a 20-nmol/L increase in 25(OH)D were 0.92 (0.88, 0.96) (P < 0.001) for total mortality, 0.96 (0.93, 0.99) (P = 0.014) (4469 events) for cardiovascular disease, 0.89 (0.85, 0.93) (P < 0.0001) (2132 events) for respiratory disease, 0.89 (0.81, 0.98) (P = 0.012) (563 events) for fractures, and 1.02 (0.99, 1.06) (P = 0.21) (3121 events) for incident total cancers., Conclusions: Plasma 25(OH)D concentrations predict subsequent lower 13-y total mortality and incident cardiovascular disease, respiratory disease, and fractures but not total incident cancers. For mortality, lowest risks were in subjects with concentrations >90 nmol/L, and there was no evidence of increased mortality at high concentrations, suggesting that a moderate increase in population mean concentrations may have potential health benefit, but <1% of the population had concentrations >120 nmol/L.

Introduction: Uric acid is the most abundant molecule with antioxidant properties found in human blood serum. We examined the relationship between serum uric acid and the incidence of respiratory disease including any effect modification by smoking status., Methods: A cohort with serum uric acid measured between 1 January 2000 and 31 December 2012 was extracted from The Health Improvement Network primary care research database. New diagnoses of COPD and lung cancer were ascertained based on diagnostic codes entered into the medical records., Results: During 1 002 496 person years (PYs) of follow-up, there were 3901 COPD diagnoses and 1015 cases of lung cancer. After multivariable adjustment, strong interactions with smoking status were detected (p<0.001) for both outcomes with significant negative relationships between serum uric acid and respiratory disease for current smokers but no strong relationships for never-smokers or ex-smokers. The relationships were strongest for lung cancer in heavy smokers (≥20 cigarettes per day) with predicted incidence rates 97 per 10 000 PYs (95% CI 68 to 126) in the lowest serum uric acid quintile (100-250 µmol/L) compared with a predicted 28 per 10 000 PYs (95% CI 14 to 41) in the highest quintile (438-700 µmol/L)., Conclusions: Low levels of serum uric acid are associated with higher rates of COPD and lung cancer in current smokers after accounting for conventional risk factors., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Collectin kidney 1 (CL-K1) is a recently identified collectin that is synthesized in most organs and circulates in blood. CL-K1 is an innate immune molecule that may play a significant role in host defense. As some collectins also play a role in coagulation, we hypothesized that an effect of CL-K1 may be apparent in disseminated intravascular coagulation (DIC), a gross derangement of the coagulation system that occurs in the setting of profound activation of the innate immune system. DIC is a grave medical condition with a high incidence of multiple organ failure and high mortality and yet there are no reliable biomarkers or risk factors. In our present study, we measured plasma CL-K1 concentration in a total of 659 specimens, including 549 DIC patients, 82 non-DIC patients and 27 healthy volunteers. The median plasma CL-K1 levels in these cohorts were 424, 238 and 245 ng/ml, respectively, with no significant difference in the latter two groups. The incidence of elevated plasma CL-K1 was significantly higher in the DIC patients compared to the non-DIC patients, resulting in an odds ratio of 1.929 (confidence interval 1.041-3.866). Infection, renal diseases, respiratory diseases, and cardiac diseases were more frequently observed in the DIC group than in the non-DIC group. In the DIC group, vascular diseases were associated with elevated plasma CL-K1 levels while age and acute illness had little effect on plasma CL-K1 levels. Independent of DIC, elevated plasma CL-K1 levels were associated with respiratory disease and coagulation disorders. These results suggest that specific diseases may affect CL-K1 synthesis in an organ dependent manner and that elevated plasma CL-K1 levels are associated with the presence of DIC. Further investigations in cohorts of patients are warranted. We propose that elevated plasma CL-K1 may be a new useful risk factor and possibly biomarker for the prediction of developing DIC.