Seasonal variations of ventricular arrhythmia clusters in defibrillator recipients

BACKGROUND: Clustering ventricular arrhythmias are the consequence of acute ventricular electrical instability and represent a challenge in the management of the growing number of patients with an implantable cardioverter-defibrillator (ICD). Triggering factors can rarely be identified. OBJECTIVES: Several studies have revealed seasonal variations in the frequency of cardiovascular events and life-threatening arrhythmias, and we sought to establish whether seasonal factors may exacerbate ventricular electrical instability leading to arrhythmia clusters and electrical storm. METHODS: Two hundred and fourteen consecutive defibrillator recipients were followed-up during 3.3 +/- 2.2 years. Arrhythmia cluster was defined as the occurrence of three or more arrhythmic events triggering appropriate defibrillator therapies within 2 weeks. Time intervals between two clusters were calculated for each month and each season, and were compared using Kruskal-Wallis test and Wilcoxon-Mann-Whitney test with Bonferroni adjustment. RESULTS: During a follow-up of 698 patient years, 98 arrhythmia clusters were observed in 51 patients; clustering ventricular arrhythmias were associated with temporal variables; they occurred more frequently in the winter and spring months than during the summer and fall. Accordingly, the time intervals between two clusters were significantly shorter during winter and spring (median and 95% CI): winter 16 (5-19), spring 11.5 (7-25), summer 34.5 (15-55), fall 50.5 (19-65), P = 0.0041. CONCLUSION: There are important seasonal variations in the incidence of arrhythmia clusters in ICD recipients. Whether these variations are related to environmental factors, change in physical activity, or psychological factors requires further study.

Alleviation of chronic venous leg ulcers with a hand-held dielectric barrier discharge plasma generator (PlasmaDerm(®) VU-2010): results of a monocentric, two-armed, open, prospective, randomized and controlled trial (NCT01415622).

BACKGROUND Cold atmospheric plasma (CAP, i.e. ionized air) is an innovating promising tool in reducing bacteria. OBJECTIVE We conducted the first clinical trial with the novel PlasmaDerm(®) VU-2010 device to assess safety and, as secondary endpoints, efficacy and applicability of 45 s/cm(2) cold atmospheric plasma as add-on therapy against chronic venous leg ulcers. METHODS From April 2011 to April 2012, 14 patients were randomized to receive standardized modern wound care (n = 7) or plasma in addition to standard care (n = 7) 3× per week for 8 weeks. The ulcer size was determined weekly (Visitrak(®) , photodocumentation). Bacterial load (bacterial swabs, contact agar plates) and pain during and between treatments (visual analogue scales) were assessed. Patients and doctors rated the applicability of plasma (questionnaires). RESULTS The plasma treatment was safe with 2 SAEs and 77 AEs approximately equally distributed among both groups (P = 0.77 and P = 1.0, Fisher's exact test). Two AEs probably related to plasma. Plasma treatment resulted in a significant reduction in lesional bacterial load (P = 0.04, Wilcoxon signed-rank test). A more than 50% ulcer size reduction was noted in 5/7 and 4/7 patients in the standard and plasma groups, respectively, and a greater size reduction occurred in the plasma group (plasma -5.3 cm(2) , standard: -3.4 cm(2) ) (non-significant, P = 0.42, log-rank test). The only ulcer that closed after 7 weeks received plasma. Patients in the plasma group quoted less pain compared to the control group. The plasma applicability was not rated inferior to standard wound care (P = 0.94, Wilcoxon-Mann-Whitney test). Physicians would recommend (P = 0.06, Wilcoxon-Mann-Whitney test) or repeat (P = 0.08, Wilcoxon-Mann-Whitney test) plasma treatment by trend. CONCLUSION Cold atmospheric plasma displays favourable antibacterial effects. We demonstrated that plasma treatment with the PlasmaDerm(®) VU-2010 device is safe and effective in patients with chronic venous leg ulcers. Thus, larger controlled trials and the development of devices with larger application surfaces are warranted.

Is a grooved collar implant design superior to a machined design regarding bone level alteration? An observational pilot study.

OBJECTIVE This retrospective observational pilot study examined differences in peri-implant bone level changes (ΔIBL) between two similar implant types differing only in the surface texture of the neck. The hypothesis tested was that ΔIBL would be greater with machined-neck implants than with groovedneck implants. METHOD AND MATERIALS 40 patients were enrolled; n = 20 implants with machined (group 1) and n = 20 implants with a rough, grooved neck (group 2), all placed in the posterior mandible. Radiographs were obtained after loading (at 3 to 9 months) and at 12 to 18 months after implant insertion. Case number calculation with respect to ΔIBL was conducted. Groups were compared using a Brunner-Langer model, the Mann-Whitney test, the Wilcoxon signed rank test, and linear model analysis. RESULTS After the 12- to 18-month observation period, mean ΔIBL was -1.11 ± 0.92 mm in group 1 and -1.25 ± 1.23 mm in group 2. ΔIBL depended significantly on time (P < .001), but not on group. In both groups, mean marginal ΔIBL was significantly less than -1.5 mm. Only insertion depth had a significant influence on the amount of periimplant bone loss (P = .013). Case number estimate testing for a difference between group 1 and 2 with a power of 90% revealed a sample size per group of 1,032 subjects. CONCLUSION ΔIBL values indicated that both implant designs fulfilled implant success criteria, and the modification of implant neck texture had no significant influence on ΔIBL.

Orthotopic Ileal Bladder Substitution in Women: Factors Influencing Urinary Incontinence and Hypercontinence.

BACKGROUND Urinary incontinence or the inability to void spontaneously after ileal orthotopic bladder substitution is a frequent finding in female patients. OBJECTIVE To evaluate how hysterectomy and nerve sparing affect functional outcomes and whether these relate to pre- and postoperative urethral pressure profile (UPP) results. DESIGN, SETTING, AND PARTICIPANTS Prospectively performed pre- and postoperative UPPs of 73 female patients who had undergone cystectomy and bladder substitution were correlated with postoperative voiding and continence status. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Outcome analyses were performed with the Kruskal-Wallis test, Wilcoxon-Mann-Whitney, or two-group post hoc testing with the Bonferroni correction. Chi-square or Fisher exact tests were applied for the categorical data. RESULTS AND LIMITATIONS Of postoperatively continent or hypercontinent patients, 22 of 43 (51.2%) had the uterus preserved; of incontinent patients, only 4 of 30 (13.3%, p<0.01) had the uterus preserved. Of postoperatively continent or hypercontinent patients, 27 of 43 patients (62.8%) had bilateral and 15 of 43 (34.9%) had unilateral attempted nerve sparing. In incontinent patients, 11 of 30 (36.7%) had bilateral and 16 of 30 (53.3%) had unilateral attempted nerve sparing (p=0.02). When compared with postoperatively incontinent patients, postoperatively continent patients had a longer functional urethral length (median: 32mm vs 24mm; p<0.001), a higher postoperative urethral closing pressure at rest (56cm H2O vs 35cm H2O; p<0.001) as well as a higher preoperative urethral closing pressure at rest (74cm H2O vs 47.5cm H2O; p=0.01). The main limitation was the limited number of patients. CONCLUSIONS In female patients undergoing radical cystectomy and bladder substitution, preservation of the uterus and attempted nerve sparing results in better functional outcomes. The preoperative UPPs correlate with postoperative voiding and continence status and may predict which patients are at a higher risk of functional failure after bladder substitution. PATIENT SUMMARY If preservation of the urethra's innervation is not possible during cystectomy, poor functional results with bladder substitutes are likely.

In vivo performance of a laser fluorescence device for the approximal detection of caries in permanent molars

OBJECTIVES: The aim of this randomised clinical trial was to investigate if a laser fluorescence device is able to discriminate between sound and carious approximal sites and between enamel and dentinal lesions, as well as to find appropriate cut-off values. METHODS: One hundred and seventeen sound or uncavitated carious sites in permanent molars were visually and radiographically examined, then either opened or not, after which their laser fluorescence was measured. Forty-three lesions were opened, the caries removed and the clinically identified caries depths were registered in addition to the radiographical scoring. Seventy-four sites were radiographically deemed sound or had enamel caries and were not opened. Here, the radiographical scorings were registered. RESULTS: Taking the radiographic scoring as gold standard for all investigated approximal sites, sound sites (D(0), n=40) showed significantly lower laser fluorescence measurements than carious sites (D(1-4), n=77) (Mann-Whitney test, P<0.025) suggesting a cut-off at 7 (sensitivity=0.68, specificity=0.7). Comparing measurements of D(0-2) (n=74) and D(3,4) (n=43), the results were also different by a statistically significant amount (P<0.025) and the cut-off calculated to be 16 (sensitivity=0.6, specificity=0.84). A fair positive correlation between laser fluorescence values and radiographical scoring was found (rho=+0.47, P<0.01). Analysing the 43 opened lesions with their clinically found lesion depths as gold standard, there was a fair positive correlation to the laser fluorescence values (rho=+0.34, P=0.03) and a moderately strong correlation to the radiographic scoring (rho=+0.67, P<0.01). CONCLUSION: The device may be an adjunct tool in the approximal detection of caries along with established procedures.

Serum concentrations of lectin-pathway components in healthy neonates, children and adults: mannan-binding lectin (MBL), M-, L-, and H-ficolin, and MBL-associated serine protease-2 (MASP-2)

This study aimed to measure serum concentrations of five lectin-pathway components, mannan-binding lectin (MBL), M-ficolin, L-ficolin, H-ficolin, and MBL-associated serine protease-2 (MASP-2), in healthy neonates and children, to determine if they change with age and to compare them with serum concentrations in healthy adults. Concentrations were measured in 141 preterm and 30 term neonates, in 120 children including infants and adolescents, and in 350 adults (97 for L-ficolin) by inhouse time-resolved immunofluorometric assays or commercially available enzyme-linked immunosorbent assays. The adjacent categories method applying Wilcoxon-Mann-Whitney tests was used to determine age categories where concentrations differed significantly. Displaying serum concentration vs. age, an inverted-U shape (higher concentrations in children than in neonates and adults) was found for MBL and the ficolins, and an S-shape for MASP-2. Serum concentrations of all five lectin-pathway components were significantly lower in preterm neonates <32-wk gestational age compared to older neonates, infants, and children. Only M-ficolin in children >1 yr and H-ficolin in term neonates and in children were found to be comparable with adult values. MBL, M-, L-, and H-ficolin, and MASP-2 serum concentrations show important changes with age. The respective normal ranges for adults should not be used in the pediatric population. The age-specific pediatric ranges established here may be used instead.

Clinical retention force development of double crowns

This study deals with the development of the retentive forces of double crowns intraorally measured. Twenty-five combined fixed-removable prostheses with a total of 84 double crowns were included in the study. The intraoral measurement was performed at 72 defined measuring points directly adjacent to the double crowns of the dentures. The measurement was performed 4-6 weeks (baseline), 6 months (recall 1), and 18 months (recall 2) after the insertion of the restoration. A specifically designed measuring device was used. The median values for the single measuring points reached 4.705 N at the baseline, 5.190 N after 6 months, and 3.740 N after 18 months. The measured values were analyzed according to differences between the median retention forces at the three defined points in time. The statistical analysis of the median values showed no statistical difference for the retention force change after 6 months but for the decrease until the second recall (Mann-Whitney test). The retention force per denture was calculated by a summation of the single measuring points. At the baseline, 12.9 N was reached. The forces did only decrease slightly and were not statistically significant. The results indicate that retention force values of double crowns, measured intraorally at the patient, do not relevantly change clinically within the first 1.5 years. Within the limitations of this study, it can be stated that wear does not influence the retentive forces of double crowns within the first 18 months. After this period the retention force should be still sufficient for denture retention.

Spinal Cord Diffusion-Tensor Imaging and Motor-evoked Potentials in Multiple Sclerosis Patients: Microstructural and Functional Asymmetry

Purpose: To assess possible association between intrinsic structural damage and clinical disability by correlating spinal cord diffusion-tensor (DT) imaging data with electrophysiological parameters in patients with a diagnosis of multiple sclerosis (MS). Materials and Methods: This study was approved by the local ethical committee according to the declaration of Helsinki and written informed consent was obtained. DT images and T1- and T2-weighted images of the spinal cord were acquired in 28 healthy volunteers and 41 MS patients. Fractional anisotropy (FA) and apparent diffusion coefficients were evaluated in normal-appearing white matter (NAWM) at the cervical level and were correlated with motor-evoked potentials (n = 34). Asymmetry index was calculated for FA values with corresponding left and right regions of interest as percentage of the absolute difference between these values relative to the sum of the respective FA values. Statistical analysis included Spearman rank correlations, Mann-Whitney test, and reliability analysis. Results: Healthy volunteers had low asymmetry index (1.5%-2.2%). In MS patients, structural abnormalities were reflected by asymmetric decrease of FA (asymmetry index: 3.6%; P = .15). Frequently asymmetrically affected among MS patients was left and right central motor conduction time (CMCT) to abductor digiti minimi muscle (ADMM) (asymmetry index, 15%-16%) and tibialis anterior muscle (TAM) (asymmetry index, 9.5%-14.1%). Statistically significant correlations of functional (ie, electrophysiological) and structural (ie, DT imaging) asymmetries were found (P = .005 for CMCT to ADMM; P = .007 for CMCT to TAM) for the cervical lateral funiculi, which comprise the crossed pyramidal tract. Interobserver reliability for DT imaging measurements was excellent (78%-87%). Conclusion: DT imaging revealed asymmetric anatomic changes in spinal cord NAWM, which corresponded to asymmetric electrophysiological deficits for both arms and legs, and reflected a specific structure-function relationship in the human spinal cord. © RSNA, 2013.

Clinical performance of a new laser fluorescence device for detection of occlusal caries lesions in permanent molars

OBJECTIVES: To determine the clinical performance of a laser fluorescence device (DIAGNOdent pen, KaVo) to discriminate between different occlusal caries depths (D(0)-D(1-4); D(0-2)-D(3,4)) in permanent molars. METHODS: In this prospective, randomized two-centre-study 120 sound/uncavitated carious sites in 120 patients were measured after visual and radiographic caries assessment. In cases of operative intervention (n=86), the lesion depths after caries removal were recorded (reference). In cases of preventive intervention (n=34), the sites were reassessed visually/radiographically after 12 months to verify the status assessed before (reference). The discrimination performance was determined statistically (Mann-Whitney test, Spearman's rho coefficient, and areas under the receiver operating characteristic curves (AUCs)). Sensitivities (SE) and specificities (SP) were plotted as a function of the measured values and cut-off values for the mentioned thresholds suggested. RESULTS: Sound sites (n=13) had significantly minor fluorescence values than carious sites (n=107) (P<0.0001) as had sites with no/enamel caries (n=63) compared to dentinal caries (n=57). The AUCs for the same discriminations were 0.92 and 0.78 (P<0.001). For the D(0)-D(1-4) threshold, a cut-off at a value of 12 (SE: 0.88, SP: 0.85) and for the D(0-2)-D(3,4) threshold at 25 (SE: 0.67, SP: 0.79) can be suggested. A moderate positive correlation between the measurements and the caries depths was calculated (rho=+0.57, P=0.01). CONCLUSION: Within this study, the device's discrimination performance for different caries depths was moderate to very good and it may be recommended as adjunct tool in the diagnosis of occlusal caries.

Adequacy of an early arterial phase low-volume contrast protocol in 64-detector computed tomography angiography for aortoiliac aneurysms

PURPOSE: This retrospective study was conducted to determine whether a low-volume contrast medium protocol provides sufficient enhancement for 64-detector computed tomography angiography (CTA) in patients with aortoiliac aneurysms. METHODS: Evaluated were 45 consecutive patients (6 women; mean age, 72 +/- 6 years) who were referred for aortoiliac computed tomography angiography between October 2005 and January 2007. Group A (22 patients; creatinine clearance, 64.2 +/- 8.1 mL/min) received 50 mL of the contrast agent. Group B (23 patients; creatinine clearance, 89.4 +/- 7.3 mL/min) received 100 mL of the contrast agent. The injection rate was 3.5 mL/s, followed by 30 mL of saline at 3.5 mL/s. Studies were performed on the same 64-detector computed tomography scanner using a real-time bolus-tracking technique. Quantitative analysis was performed by determination of mean vascular attenuation at 10 regions of interest from the suprarenal aorta to the common femoral artery by one reader blinded to type and amount of contrast agent and compared using the Student t test. Image quality according to a 4-point scale was assessed in consensus by two readers blinded to type and amount of contrast medium and compared using the Mann-Whitney test. Multivariable adjustments were performed using ordinal regression analysis. RESULTS: Mean total attenuation did not differ significantly between both groups (196.5 +/- 33.0 Hounsfield unit [HU] in group A and 203.1 +/- 44.2 HU in group B; P = .57 by univariate and P > .05 by multivariable analysis). Accordingly, attenuation at each region of interest was not significantly different (P > .35). Image quality was excellent or good in all patients. No significant differences in visual assessment were found comparing both contrast medium protocols (P > .05 by univariate and by multivariable analysis). CONCLUSIONS: Aortoiliac aneurysm imaging can be performed with substantially reduced amounts of contrast medium using 64-detector computed tomography angiography technology.

Losses of chromosome arms 4q, 8p, 13q and gain of 8q are correlated with increasing chromosomal instability in hepatocellular carcinoma

OBJECTIVE: Chromosomal instability is a key feature in hepatocellular carcinoma (HCC). Array comparative genomic hybridization (aCGH) revealed recurring structural aberrations, whereas fluorescence in situ hybridization (FISH) indicated an increasing number of numerical aberrations in dedifferentiating HCC. Therefore, we examined whether there was a correlation between structural and numerical aberrations of chromosomal instability in HCC. METHODS AND RESULTS: 27 HCC (5 well, 10 moderately, 12 lower differentiated) already cytogenetically characterized by aCGH were analyzed. FISH analysis using probes for chromosomes 1, 3, 7, 8 and 17 revealed 1.46-4.24 signals/nucleus, which correlated with the histological grade (well vs. moderately,p < 0.0003; moderately vs. lower, p < 0.004). The number of chromosomes to each other was stable with exceptions only seen for chromosome 8. Loss of 4q and 13q, respectively, were correlated with the number of aberrations detected by aCGH (p < 0.001, p < 0.005; Mann-Whitney test). Loss of 4q and gain of 8q were correlated with an increasing number of numerical aberrations detected by FISH (p < 0.020, p < 0.031). Loss of 8p was correlated with the number of structural imbalances seen in aCGH (p < 0.048), but not with the number of numerical changes seen in FISH. CONCLUSION: We found that losses of 4q, 8p and 13q were closely correlated with an increasing number of aberrations detected by aCGH, whereas a loss of 4q and a gain of 8q were also observed in the context of polyploidization, the cytogenetic correlate of morphological dedifferentiation.

Dental phobia is no contraindication for oral implant therapy

OBJECTIVES Dental phobia is a psychological disease and a possible contraindication for implant therapy. The study aimed to show that implant therapy in dental-phobic patients (DP, test group) after adequate psychological and dental pretreatment (PDPT) is successfully possible and results in a similar implant prognosis as in nonfearful patients (NF, control group). METHOD AND MATERIALS 15 DP with PDPT and 15 NF were treated with dental implants and were re-evaluated 2 to 4 years after denture-mounting regarding: alteration of dental anxiety (Hierarchical Anxiety Questionnaire [HAQ], Visual Analog Scale [VAS]), patient satisfaction and compliance, implant success, and peri-implant health. Statistical tests of non-inferiority DP versus NF were performed with Hodges-Lehmann estimators and respective one-sided 97.5% confidence intervals of Moses, and pairwise testings with Mann-Whitney test. RESULTS The DP test group rated its anxiety significantly lower at follow- up than at baseline (PHAQ < .001). However, at follow-up, anxiety was still higher in DP than in NF (PHAQ = .046; PVAS < .001). Implant success at follow-up was 100%. Oral health was equally good in DP and NF patients. At follow-up, all patients were satisfied with implant therapy, but compliance was better for NF (100%) than for DP (73% dental checkup; 67% dental hygienist). CONCLUSION Implant therapy can be successfully performed in DP patients with PDPT as phobia is not negatively influenced by the invasive implant therapy. However, motivation for professional maintenance programs remains challenging.

Effect of nonsurgical periodontal treatment in conjunction with either systemic administration of amoxicillin and metronidazole or additional photodynamic therapy on the concentration of matrix metalloproteinases 8 and 9 in gingival crevicular fluid in patients with aggressive periodontitis.

BACKGROUND To evaluate in patients with aggressive periodontitis (AgP) the effect of nonsurgical periodontal treatment in conjunction with either additional administration of systemic antibiotics (AB) or application of photodynamic therapy (PDT) on the gingival crevicular fluid (GCF) concentration of matrix metalloproteinases 8 and 9 (MMP-8 and -9). METHODS Thirty-six patients with AgP were included in the study. Patients were randomly assigned to treatment with either scaling and root planing (SRP) followed by systemic administration of AB (e.g. Amoxicillin + Metronidazole) or SRP + PDT. The analysis of MMP-8 and -9 GCF concentrations was performed at baseline and at 3 and 6 months after treatment. Nonparametric U-Mann-Whitney test was used for comparison between groups. Changes from baseline to 3 and 6 months were analyzed with the Friedman's ANOVA test with Kendall's index of consistency. RESULTS In the AB group, patients showed a statistically significant (p = 0.01) decrease of MMP-8 GCF level at both 3 and 6 months post treatment. In the PDT group, the change of MMP-8 GCF level was not statistically significant. Both groups showed at 3 and 6 months a decrease in MMP-9 levels. However, this change did not reach statistical significance. CONCLUSIONS Within the limits of the present study, it may be suggested that in patients with AgP, nonsurgical periodontal therapy in conjunction with adjunctive systemic administration of amoxicilin and metronidazole is more effective in reducing GCF MMP-8 levels compared to the adjunctive use of PDT.

A new standardized treadmill walking test requiring low motor skills in children aged 4-10 years

Exercise intolerance may be reported by parents of young children with respiratory diseases. There is, however, a lack of standardized exercise protocols which allow verification of these reports especially in younger children. Consequently the aims of this pilot study were to develop a standardized treadmill walking test for children aged 4-10 years demanding low sensorimotor skills and achieving high physical exhaustion. In a prospective experimental cross sectional pilot study, 33 healthy Caucasian children were separated into three groups: G1 (4-6 years, n = 10), G2 (7-8 years, n = 12), and G3 (9-10 years, n = 11). Children performed the treadmill walking test with increasing exercise levels up to peak condition with maximal exhaustion. Gas exchange, heart rate, and lactate were measured during the test, spirometry before and after. Parameters were statistically calculated at all exercise levels as well as at 2 and 4 mmol/L lactate level for group differences (Kruskal-Wallis H-test, alpha = 0.05; post hoc: Mann-Whitney U-test with Bonferroni correction alpha = 0.05/n) and test-retest differences (Wilcoxon-rank-sum test) with SPSS. The treadmill walking test could be demonstrated to be feasible with a good repeatability within groups for most of the parameters. All children achieved a high exhaustion level. At peak level under exhaustion condition only the absolute VO2 and VCO2 differed significantly between age groups. In conclusion this newly designed treadmill walking test indicates a good feasibility, safety, and repeatability. It suggests the potential usefulness of exercise capacity monitoring for children aged from early 4 to 10 years. Various applications and test modifications will be investigated in further studies.

Effect of smoking on the results of a chlorhexidine digluconate treatment extended up to 3 months after scaling and root planing-a pilot study

The aim of the study was to evaluate the impact of smoking on a prolongated chlorhexidine digluconate regimen after scaling and root planing. Forty-two smokers (test group) and 85 nonsmoking patients (control group) with generalized chronic periodontitis were examined for clinical attachment level (CAL), probing depth (PD), bleeding on probing (BoP), and Plaque Index (Pl) at baseline and after 1 and 3 months. During scaling and root planing, a 0.2% chlorhexidine digluconate solution and a 1% chlorhexidine digluconate gel were used. The subjects used a 0.2% chlorhexidine digluconate solution twice daily for 3 months. The Mann-Whitney U and Wilcoxon tests were used for statistical analysis. There were significant improvements of all studied variables after 1 and 3 months in both groups. After 3 months, the mean improvement in the test group was 1.62 mm for CAL, 2.85 mm for PD, and 48% for BoP; in the control group, the values were 2.18 mm for CAL, 2.81 mm for PD, and 47% for BoP. Only the maximum changes of CAL between 1 and 3 months (test group, 0.32 mm vs 0.69 mm in the control group) and PD (test group, 0.47 mm vs 0.76 mm in the control group) were significantly different between the groups (P < .05 and P = .05, respectively). The present data appear to suggest that the use of chlorhexidine digluconate twice daily during a period of 3 months following nonsurgical periodontal therapy may result in significant clinical improvements in smokers and nonsmokers.