Individuals with filaggrin-related eczema and asthma have increased long-term medication and hospital admission costs.

BACKGROUND: Eczema and asthma are chronic diseases with onset usually before the age of 5 years. More than 50% of individuals with eczema will develop asthma and/or other allergic diseases. Several loss-of-function mutations in filaggrin (FLG) have been identified in patients with eczema. However, the association of FLG with healthcare use is unknown. OBJECTIVES: To determine whether FLG mutations are associated with increased prescribing for eczema and asthma and whether increased prescribing is associated with increased healthcare costs. METHODS: A secondary analysis of BREATHE, a cross-sectional study of gene-environment associations with asthma severity, was undertaken. BREATHE data was collected for 1100 participants with asthma, in Tayside and Fife, Scotland during the period 2003-2005. Through collaboration with the Health Informatics Centre in Dundee, BREATHE was linked to accident and emergency, community prescribing and Scottish morbidity records. The data linkage allowed longitudinal exploration of associations between genetic variation and prescribing. RESULTS: An association was found between FLG mutations and increased prescribing for mild and moderate eczema, asthma-reliever medicine and asthma exacerbations. A strong association was found between FLG mutations and prescribing of emollients [incidence rate ratio (IRR) 2·19, 95% confidence interval (CI) 1·36-3·52], treatment for severe eczema (IRR 2·18, 95% CI 1·22-3·91) and a combination of a long-acting ß2 -agonist and corticosteroids (IRR 3·29, 95% CI 1·68-6·43). CONCLUSIONS: The presence of FLG mutations in this cohort is associated with increased prescribing for eczema and asthma. Randomized controlled trials are required to determine if these individuals could benefit from management strategies to reduce morbidity and treatment costs.

Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults.

BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed. RESULTS: Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively. CONCLUSION AND CLINICAL RELEVANCE: A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid-treated asthmatic children.

BACKGROUND: The T2206C FCER2 variant was found previously to be associated with IgE levels, exacerbation rates and decreased FCER2 expression in children on inhaled corticosteroids (ICS) participating in a clinical trial. This finding has not been replicated. We sought to replicate the association between the FCER2 gene and exacerbations in children with asthma. In addition, we tested the hypothesis that the T2206C variant may be associated with other markers of steroid resistance such as asthma symptom scores and asthma medication use. METHODS: The influence of the T2206C variant on asthma exacerbations (emergency department visits or hospitalization), symptoms scores and medication use was explored using data from two populations of asthmatic children using ICS: Pharmacogenetics of Asthma medication in Children: Medication with ANti-inflammatory effects study (n = 386) and BREATHE study (n = 939). RESULTS: The T2206C variant was associated with increased risk of asthma-related hospital visits in both cohorts (OR: 1.91, 95% CI: 1.08-3.40), and meta-analysis with previously published results was highly significant (OR: 2.38, 95% CI: 1.47-3.85, P = 0.0004). The FCER2 variant was also associated with increased risk of uncontrolled asthma measured by Asthma Control Questionnaire (OR: 2.64, 95% CI: 1.00-6.98) and was associated with increased daily steroid dose (OR: 2.46, 95% CI: 1.38-4.39). CONCLUSION: The association between the FCER2 T2206C variant and asthma-related hospitalizations in steroid-treated asthma appears robust and may also be associated with other indicators of lack of ICS efficacy such as asthma symptoms and a requirement for higher daily doses of ICS. Our results suggest that the FCER2 T2206C variant might be a useful pharmacogenetic predictor of steroid refractory patients.

Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: a go-DARTS study.

SLCO1B1 gene variants are associated with severe statin-induced myopathy. We examined whether these variants are also associated with general statin intolerance in a large population of patients with type 2 diabetes receiving statins as part of routine clinical care. A total of 4,196 individuals were genotyped for rs4149056 (Val174Ala) and rs2306283 (Asp130Asn). Intolerance was defined by serum biochemistry and also by discontinuation, switching, or reduction in dose of the prescribed statin drug. Ala174 was associated with higher intolerance (odds ratio = 2.05, P = 0.043), whereas Asp130 was associated with lower intolerance (odds ratio = 0.71, P = 0.026). Ala174 was associated with a lower low-density lipoprotein cholesterol (LDLc) response to statins (P = 0.01) whereas 130D was associated with a greater LDLc response to statins (P = 0.048), as previously reported; however, this association was no longer present when data for statin-intolerant individuals were removed from the analysis. This study suggests that common genetic variants selected for an extreme phenotype of statin-induced myopathy also predispose to more common milder statin intolerance and may, for this reason, impact lipid-lowering efficacy.

Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: a Go-DARTS study.

Sulfonylureas are metabolized mainly by the cytochrome p450 2C9 (CYP2C9) enzyme. Two CYP2C9 variants--*2 (Arg144Cys) and *3 (Ile359Leu)--are associated with reduced enzyme activity and impaired substrate metabolism. We identified 1,073 incident users of sulfonylureas in Tayside, Scotland, and assessed the impact of the combined CYP2C9*2 and CYP2C9*3 genotypes on early and sustained sulfonylurea response. We found that patients with two copies of a loss-of-function allele were 3.4 times (P = 0.0009) more likely to achieve a treatment hemoglobin A(1c) (HbA(1c)) level <7% than patients with two wild-type CYP2C9 alleles. This corresponds to a 0.5% (P = 0.003) greater reduction in HbA(1c) concentration. In addition, *2 and *3 allele carriers were less likely to experience treatment failure with sulfonylurea monotherapy (P = 0.04; per-allele hazard ratio 0.79; 95% confidence interval 0.63-0.99). In conclusion, CYP2C9 loss-of-function alleles are associated with greater response to sulfonylureas and decreased failure of therapy consistent with the pharmacokinetic role of CYP2C9.

Sudden unexpected death in heart failure may be preceded by short term, intraindividual increases in inflammation and in autonomic dysfunction: a pilot study.

OBJECTIVE: To see whether sudden unexpected death in chronic heart failure is preceded by intraindividual worsening in inflammation and in ECG criteria. DESIGN AND SETTING: Prospective cohort study conducted in the community. PATIENTS: 34 patients with chronic heart failure were studied. Their mean (SD) age was 68 (8) years, 29 were men, mean (SD) left ventricular ejection fraction was 29 (9)%, and they were in New York Heart Association functional class II (n = 20), III (n = 11), and IV (n = 3). The patients were examined monthly over 24 months, with sequential measurement of C reactive protein and neutrophil counts and 24 hour ambulatory ECG monitoring measuring heart rate variability, mean heart rate, and arrhythmias. Intraindividual changes in these parameters were related to subsequent cardiac deaths. RESULTS: During follow up, nine patients died: five patients had a sudden unexpected death (SUD) and four died of progressive heart failure (PHF). There were significant intraindividual changes in neutrophil counts (p = 0.02), C reactive protein (p = 0.039), and heart rate variability (p < or = 0.018) in those who died of SUD and PHF. In contrast no significant changes were seen in ventricular extrasystoles, ventricular tachycardia episodes, brain natriuretic peptide, or aldosterone in the SUD group, but all of these parameters did increase as expected in those who died of PHF. CONCLUSIONS: This is preliminary evidence that SUD may be preceded by intraindividual increases in both inflammation and autonomic dysfunction. Both may be causal in genesis but, even if they are not, intraindividual increases in either may be convenient markers to identify patients at high risk of impending SUD. Larger studies are needed to confirm the observation from this pilot study.

Measurement of passive smoking in adults: self-reported questionnaire or serum cotinine?

BACKGROUND: Low to moderate agreement between self-reported exposure to environmental tobacco smoke (ETS) and serum cotinine levels in non-smokers questions the accuracy of the measurement of ETS exposure. We examined the relationship of serum cotinine to different self-reported ETS questionnaires in a large community-based study. METHODS: Subjects were derived from four Scottish MONICA surveys. Agreement between self-reported ETS (yes/no) and serum cotinine levels (> 0, 0) in non-smokers was tested by K, and the difference in cotinine levels among self-reported ETS exposure by ANOVA and the relationship by linear regression. RESULTS: None of the values for K was > 0.24 for any ETS questionnaire. In non-smokers with serum cotinine > 0, cotinine levels increased with increasing ETS exposures. In the first and second surveys with the questionnaire of ETS exposure in the last 3 days, standardised coefficients were 0.28-0.39, while in the third and fourth surveys with the questionnaire of a total exposure to ETS at work, at home and in other places the standardised coefficients were 0.19-0.36, with the questionnaire of ETS daily exposure hours, 0.23-0.36. The relationship between self-reported ETS and cotinine levels varied with the questionnaires, and with the time of day of the blood sample collection. In current smokers, cotinine levels were significantly related to both the number of cigarettes smoked daily (the coefficients were 0.13-0.41) and time elapsed since the last cigarette (-0.24 to -0.40). CONCLUSION: The findings raise the question of whether it is ideal to take only serum cotinine as an index of ETS exposure in adults, because of time delays between ETS exposure and blood collection, and suggest the combined use of appropriately worded self-reported questionnaires and cotinine levels to estimate ETS exposure.

Serological markers of Chlamydia pneumoniae infection in men and women and subsequent coronary events; the Scottish Heart Health Study Cohort.

AIMS: To investigate the relationship between serum markers of Chlamydia pneumoniae infection and subsequent coronary events. METHODS AND RESULTS: In a nested case-control study, based on the Scottish Heart Health Study cohort, we estimated IgG, IgA and IgM antibodies to C. pneumoniae, and circulating immune complexes containing C. pneumoniae antigen in baseline serum samples from 217 cases experiencing a subsequent coronary event during follow-up (mean 7.5 years) and from their matched controls. In men, the proportion of specimens positive for IgG, IgA and IgM antibodies showed no case-control differences (80% vs 80%, 57% vs 53% and 3% vs 3%, respectively). The odds ratio for a coronary event was 1.00 (95% confidence interval 0.59-1.69) for the presence of IgG antibodies to C. pneumoniae; 1.21 (0.76-1.92) for IgA and 0.75 (0.17-3.35) for IgM. Similar results were seen in women. The proportion of specimens with circulating immune complexes with C. pneumoniae antigen also showed no case-control differences (12% vs 12%, both sexes combined) with an odds ratio of 1.00 (0.57-1.76). CONCLUSION: Prior infection with C. pneumoniae, as estimated by these markers, does not appear to be a risk factor for subsequent coronary heart disease.

Environmental tobacco smoke and lung function in employees who never smoked: the Scottish MONICA study.

OBJECTIVES: To investigate the relation between lung function in employees and exposure to environmental tobacco smoke (ETS) at work and elsewhere. METHODS: Never smokers in employment (301) were identified from the fourth Scottish MONICA survey. They completed a self administered health record, which included details of exposure to ETS, and attended a survey clinic for physical and lung function measurements, and for venepuncture for estimation of serum cotinine. Differences in lung function in groups exposed to ETS were tested by analysis of variance (ANOVA), the exposure-response relation by a linear regression model, and a case-control analysis undertaken with a logistic regression model. RESULTS: Both men and women showed effects on forced expiratory volume in the first second (FEV(1)) and forced vital capacity (FVC) from exposure to ETS-higher exposure going with poorer lung function. This was found at work, and in total exposure estimated from ETS at work, at home, and at other places. Linear regression showed an exposure-response relation, significant for ETS at work, total exposure, and exposure time/day, but not at home or elsewhere. Compared with those not exposed to ETS at work, those who were exposed a lot had a 254 ml (95% confidence interval (95% CI) 84 to 420) reduction in FEV(1), and a 273 ml (60 to 480) reduction in FVC after adjusting for confounders. Although lung function was not significantly associated with serum cotinine in all the data, a significant inverse relation between cotinine concentration and FVC occurred in men who had had blood collected in the morning. Case-control analysis also showed a significant exposure-response relation between ETS, mainly at work, and lung function. A higher exposure measured both by self report and serum cotinine went with lower lung function. CONCLUSION: The exposure-response relation shows a reduction in pulmonary function of workers associated with passive smoking, mainly at work. These findings endorse current policies of strictly limiting smoking in shared areas, particularly working environments.

Plasma vitamin C and food choice in the third Glasgow MONICA population survey.

STUDY OBJECTIVE: To determine the contribution of different foods to the estimated intakes of vitamin C among those differing in plasma vitamin C levels, and thereby inform dietary strategies for correcting possible deficiency. DESIGN: Cross sectional random population survey. SETTING: North Glasgow, Scotland, 1992. PARTICIPANTS: 632 men and 635 women, aged 25 to 74 years, not taking vitamin supplements, who participated in the third MONICA study (population survey monitoring trends and determinants of cardiovascular disease). MEASUREMENTS AND MAIN RESULTS: Dietary and sociodemographic information was collected using a food frequency and lifestyle questionnaire. Plasma vitamin C was measured in non-fasted venous blood samples and subjects categorised by cut points of 11.4 and 22.7 micromol/l as being of low, marginal or optimal vitamin C status. Food sources of dietary vitamin C were identified for subjects in these categories. Plasma vitamin C concentrations were compared among groups classified according to intake of key foods. More men (26%) than women (14%) were in the low category for vitamin C status; as were a higher percentage of smokers and of those in the older age groups. Intake of vitamin C from potatoes and chips (fried potatoes) was uniform across categories; while the determinants of optimal versus low status were the intakes of citrus fruit, non-citrus fruit and fruit juice. Optimal status was achieved by a combined frequency of fruit, vegetables and/or fruit juice of three times a day or more except in older male smokers where a frequency greater than this was required even to reach a marginal plasma vitamin C level. CONCLUSION: Fruit, vegetables and/or fruit juice three or more times a day increases plasma vitamin C concentrations above the threshold for risk of deficiency.

Evidence for age-related differences in the fatty acid composition of human adipose tissue, independent of diet.

OBJECTIVE: To test the null-hypothesis that no age difference in adipose tissue fatty acid composition exists independent of dietary fat intake. DESIGN: A cross-sectional survey of coronary heart disease risk factors, the Scottish Heart Health Study, provided needle biopsy adipose tissue fatty acid data and food frequency-derived dietary data. SETTING: Twenty-two Scottish Districts between 1984 and 1986. SUBJECTS: A total of 10,359 men and women aged 40-59 y were randomly recruited in sex and five-year age bands from GP lists. A sub-set of 2308 men and 2049 women (42%) provided satisfactory adipose tissue and dietary data. MAIN OUTCOME AND MEASURES: Multiple regression analysis (adjusting for dietary fats, body mass index and smoking, with and without menopause status for women) of the relationship between individual fatty acids in adipose tissue and age, and between age and the ratio of linoleic acid (C18:2, n-6) to gamma-linolenic acid (C18:3, n-6) as an indicator of delta-6 desaturase activity. RESULTS: Sex-consistent changes with age occurred for linoleate (adjusted regression slope +/- s.e. for men -0.299 +/- 0.1339 and for women -0.504 +/- 0.1731) and gamma-linolenate (adjusted regression slope +/- s.e. for men -0.141 +/- 0.0341 and for women -0.154 +/- 0.0469) both P < 0.0001. These changes gave rise to a significant increase (P < or = 0.005) in the C18:2, n-6 to C18:3, n-6 ratio with age). Dihomo-gamma-linolenic acid (C20:3, n-6) and docosahexa- plus docosapentaenoic acids (C22:5 + C22:6, n-3) also increased significantly with age (P < or = 0.01). For the latter, the adjusted regression slopes were far greater for women (0.596 +/- 0.0575) than men (0.131 +/- 0.0417). CONCLUSIONS: The results show that ageing does influence adipose tissue fatty acid composition independent of diet. The sex differences may partially be due to inadequate adjustment for changes in sex hormone status in males with ageing. Using the current indicator, a decline in the rate limiting step of beta-6 desaturation appeared to occur with age, and was greater in women than in men. These results may indicate that an increase in dietary gamma-linolenic acid (C18:3, n-6) is necessary with age to offset the relative imbalance between PUFA levels which appears to occur. However, any direct health benefit regarding the common diseases of ageing from such a strategy still remain to be clarified.

Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish Heart Health Study: cohort study.

OBJECTIVE: To compare prediction by 27 different factors in men and women of coronary heart disease events, coronary deaths, and deaths from all causes. DESIGN: Cohort study. SETTING: Scottish population study. SUBJECTS: In 1984-7 random sampling of residents aged 40-59 produced 11,629 men and women who generated survey clinic questionnaires, examination findings, and blood and urine specimens. MAIN OUTCOME MEASURES: Subsequent death, coronary artery surgery, and myocardial infarction. Risks were calculated for each category of factor or fifth of continuous variables. 27 factors were ranked by descending age adjusted hazard ratio of the top to bottom class in each factor, by sex and end point. RESULTS: Follow up averaged 7.6 years, during which the 5754 men had 404 coronary events, 159 coronary deaths, and 383 deaths and the 5875 women 177, 47, and 208 respectively. The rankings for factors for the three end points were mainly similar in men and women, although hazard ratios were often higher in women. Classical risk factors ranked better for predicting coronary risk than newer ones. Yet strong prediction of coronary risk was no guarantee of significant prediction of all cause mortality. Findings included an anomalous coronary protective role for type A behaviour in women; raised plasma fibrinogen as a strong predictor of all end points; and an unexpectedly powerful protective relation of dietary potassium to all cause mortality. CONCLUSIONS: These initial unifactorial rankings and comparisons must be interpreted with caution until potential interaction, confounding, and problems of measurement and causation are further explored.

Passive smoking by self report and serum cotinine and the prevalence of respiratory and coronary heart disease in the Scottish heart health study.

STUDY OBJECTIVE: To explore the relationship between self reported environmental tobacco smoke exposure (or passive smoking), the serum cotinine concentration, and evidence of respiratory or coronary disease in men and women who have never smoked. DESIGN: Cross sectional random population survey identifying disease markers and relating them to measures of passive smoking. Disease markers were previous medical diagnoses, response to standard symptom questionnaires, and electrocardiographic signs. SETTING: Samples of men and women aged 40-59 years drawn from general practitioner lists in 22 local government districts of Scotland, between 1984 and 1986. PARTICIPANTS: A total of 786 men and 1492 women who reported never having smoked tobacco, and who had serum cotinine concentrations below 17.5 ng/ml, the cut off point for smoking "deceivers", took part. RESULTS: Fewer than one third of never smokers reported no recent exposure to environmental tobacco smoke and the same proportion had no detectable cotinine. Women had lower cotinine values than men but reported more exposure to smoke. The correlation between the measures of exposure was poor. Self-reported exposure showed strong, statistically significant, dose response relationships with respiratory symptoms and with the coronary disease markers. These relationships were weak or absent for serum cotinine, except for diagnosed coronary heart disease. Here the dose response gradient was as strong as that for self report, with an odds ratio of 2.7 (95% CI 1.3, 5.6) for the highest v the lowest exposure group, adjusted for age, housing tenure, total cholesterol, and blood pressure, and not explained by fibrinogen. CONCLUSIONS: The validity of different measures of tobacco smoke exposure needs further investigation. The gradient of diagnosed coronary heart disease with both self reported exposure and serum cotinine was, however, surprisingly strong, statistically significant, and unexplained by other factors. These findings reinforce current policies to limit passive tobacco smoke exposure.

Beta-adrenoceptor antagonists enhance white blood cell aggregation in patients with ischaemic heart disease.

The effects of beta-adrenoceptor antagonists, calcium channel blockers and long acting nitrates on white blood cell (WBC) aggregation were studied in patients with ischaemic heart disease. WBC aggregation was significantly increased by beta-adrenoceptor antagonists (P = 0.011) but was unaffected by either calcium channel blockers or long acting nitrates. Enhanced WBC aggregation promotes microvascular occlusion and damage.

Adipose tissue fatty acids in Scottish men and women: results from the Scottish Heart Health Study.

The fatty acid composition of adipose tissue from 4114 men and women across 22 districts of Scotland is described. A biopsy of subcutaneous adipose tissue was obtained from the upper arm using a skin biopsy punch. Overall the proportion of saturated fatty acids was lower in women and those of monounsaturated and polyunsaturated higher than in men. There were significant effects of age on adipose tissue fatty acid composition, particularly in women, where the proportion of saturated fatty acids decreased and that of monounsaturated fatty acids increased with advancing age. The fatty acid composition of adipose tissue varied among the districts studied. The district standardised mortality ratio for coronary heart disease was positively correlated with the district mean oleic acid value and inversely correlated with the district mean linoleic acid value. This paper supports the importance of adipose tissue fatty acids as indicators of risk factor status for coronary heart disease.

Smoking characteristics and inhalation biochemistry in the Scottish population.

Data from a cross-sectional random population sample of 10,359 middle-aged Scottish men and women are used to investigate the relationships between self-reported tobacco consumption and three biochemical markers of tobacco inhalation: expired air carbon monoxide (CO), serum thiocyanate and serum cotinine. These data represent one of the largest samples of these biochemical markers yet analysed. The results show that, for each sex, the biochemical markers are highly correlated for smokers and for the entire sample of mixed smokers and non-smokers. CO is the preferred biochemical marker, in such groups, because it is the cheapest, is non-invasive and gives virtually instantaneous results. Self-reported daily cigarette consumption also correlates well with each of these biochemical markers, and so it appears that people are, in the context of population studies, mainly truthful about their smoking. The relationships with self-reported cigarette consumption are curvilinear with apparent levelling out of the gradient at around 25 cigarettes/day for cotinine and thiocyanate and at greater than 40 cigarettes/day for CO. Sex differences are small, although thiocyanate is generally higher and cotinine generally lower in women with the same self-reported cigarette consumption as men. Amongst non-smokers, only cotinine is able to discriminate between self-reported levels of exposure to passive smoking. CO and thiocyanate are not suitable for measuring low levels of smoke inhalation, such as found in passive smokers.