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Biomedical subjects

Jean-Pierre Zellweger

Publications and source records attributed to Jean-Pierre Zellweger.

At least 19 recordsLinked to original sources

Diagnostic yield of sputum, induced sputum, and bronchoscopy after radiologic tuberculosis screening.

RATIONALE: To assess feasibility and yield of diagnostic procedures after active case finding for tuberculosis with radiologic screening at the three main entry points for asylum seekers to Switzerland. METHOD: Prospective multicenter study on the value of symptoms, spontaneous and induced sputum, and bronchoscopy for the confirmation of tuberculosis in radiologically selected cases. RESULTS: Among 101 asylum seekers examined, spontaneous sputum was collected "on the spot" in 83 and yielded 7 (54%) of 13 smear-positive and 13 (39%) of 33 culture-positive cases. Morning sputum, collected in 84, yielded 8 (62%) and 16 (49%), and the two spontaneous sputa combined 9 (69%) and 20 (61%), respectively. Two additional induced sputa, collected in 91 persons, yielded no additional smear-positive, but yielded seven culture-positive cases (yield, 82%). Bronchoscopy, performed in 87 of 92 sputum smear-negative cases, yielded four additional smear-positive and six culture-positive cases. Culture confirmation was independently and significantly predicted by obtaining a specimen using bronchoscopy (adjusted odds ratio, 11.0; 95% confidence interval, 1.9-62) and a prior decision to treat (adjusted odds ratio, 3.0; confidence interval, 1.1-8.1). CONCLUSION: Radiographic anomalies compatible with tuberculosis found during screening are a poor guide to initiation of treatment. Respiratory and systemic symptoms correlated weakly with culture confirmation of tuberculosis. All radiologically selected cases must be examined with on-the-spot and early-morning sputum, regardless of symptoms. If both specimens are smear negative, the yield is increased by bronchoscopy and, to a lesser extent, by two samples of induced sputum. The examination of any single specimen has a low yield of 36 to 63% and is insufficient to exclude active tuberculosis.

Adolescent↗

[Epidemiogy and treatment of tuberculosis in Switzerland].

Problems in tuberculosis are its rarity, drug-resistant strains, and patients' social aspects. Knowing the epidemiology helps to "think tuberculosis" when some anamnestic and clinical findings are present. In a not too seriously ill patient, the emergency consists of excluding infectious tuberculosis by sputum smear examinations. A positive result will lead to the patient's isolation and the initiation of treatment. Negative smears allow to wait for culture results, while following the patient and repeating smears after a non-specific antibiotic treatment. In case of strong suspicion of tuberculosis or risk for a rapid progression, the treatment should begin without delay. Discussion with a specialist is often warranted. A follow-up by the Swiss Pulmonary Association is recommended to prevent the patient from defaulting from treatment.

Adolescent↗

Respiratory effects of environmental tobacco exposure are enhanced by bronchial hyperreactivity.

RATIONALE: Exposure to environmental tobacco smoke (ETS) is associated with increased reports of respiratory symptoms and reduced lung function, but the long-term effects of ETS are unclear, notably in healthy individuals with bronchial hyperresponsiveness (BHR). OBJECTIVE: To assess the longitudinal effects of ETS exposure on the development of respiratory symptoms and spirometry in subjects with BHR. METHODS: The study population included 1,661 never-smokers from the SAPALDIA (Swiss Study on Air Pollution and Lung Diseases in Adults) cohort, assessed in 1991 (baseline) and 11 yr later, who were symptom-free at baseline. Incident reports of respiratory symptoms and results of spirometry were assessed at the follow-up survey. MAIN RESULTS: Exposure to ETS reported in the two surveys was strongly associated with the development of cough (odds ratio, 2.1; 95% confidence interval, 1.2-3.7; p = 0.01). In subjects with BHR exposed to ETS at both surveys, a trend for strong associations were observed for wheeze, cough, dyspnea, and chronic bronchitis; however, the association reached statistical significance only for the symptom of dyspnea (p < 0.01). Lower FEV1/FVC (mean +/- SD, 72.9 +/- 7.7 vs. 76.8 +/- 6.1%; p < 0.01) and FEF(25-75) (forced expiratory flow, midexpiratory phase)/FVC (mean +/- SD, 56.1 +/- 22.5 vs. 68.1 +/- 21.6%; p < 0.01) were observed in subjects with BHR exposed to ETS compared with nonexposed subjects without BHR. Lower values were found in subjects continuing exposure by the follow-up survey. CONCLUSION: Exposure to ETS was strongly associated with the development of respiratory symptoms in previously asymptomatic subjects with BHR within 11 yr. Furthermore, subjects with underlying BHR had reduced lung function at follow-up, thus suggesting a higher risk for the development of chronic respiratory disease in this subset of the population.

Adult↗

T-SPOT.TB: an in vitro diagnostic assay measuring T-cell reaction to Mycobacterium tuberculosis-specific antigens.

The overall sensitivity of the RD1 ELISPOT assay (T-SPO.TB), which counts T cells sensitized to specific Mycobacterium tuberculosis peptide sequences, was 81-97% in populations with confirmed tuberculosis, in whom 39-78% had immunosuppressive conditions. In patients with confirmed tuberculosis, the respective RD1 ELISPOT versus tuberculin skin test (TST) sensitivities were 100% versus 89% in adults and 77% versus 35% in children (of whom 39% were HIV-positive). In contrast to that of the TST, the sensitivity of the RD1 ELISPOT assay was not significantly affected by age <36 months, or the immunological or nutritional status of the subjects. Specificity was 100% in two UK-based studies. Isolated false positives have been recorded in patients infected with non-tuberculous M. kansasii. A study investigating latent tuberculosis infection found no significant difference in results between HIV-positive and -negative participants for the RD1 ELISPOT assay, while the TST varied significantly with HIV status. Contact-tracing studies have demonstrated concordance between the RD1 ELISPOT assay and the TST of 65-89%. There is a significant correlation between a positive result and the degree of exposure to the index case for the RD1 ELISPOT assay, but not for the TST, in contact-tracing studies. Unlike the TST, the RD1 ELISPOT assay is not confounded by bacille Calmette-Guérin vaccination.

Antigens, Bacterial↗

Risk factors for positive tuberculin skin tests among migrant and resident children in Lausanne, Switzerland.

SETTING: Ambulatory paediatric clinic in Lausanne, Switzerland, a country with a significant proportion of tuberculosis (TB) among immigrants. AIM: To assess the factors associated with positive tuberculin skin tests (TST) among children examined during a health check-up or during TB contact tracing, notably the influence of BCG vaccination (Bacille Calmette Guérin) and history of TB contact. METHOD: A descriptive study of children who had a TST (2 Units RT23) between November 2002 and April 2004. Age, sex, history of TB contact, BCG vaccination status, country of origin and birth outside Switzerland were recorded. RESULTS: Of 234 children, 176 (75%) had a reaction equal to zero and 31 (13%) tested positive (>10 mm). In a linear regression model, the size of the TST varied significantly according to the history of TB contact, age, TB incidence in the country of origin and BCG vaccination status but not according to sex or birth in or outside Switzerland. In a logistic regression model including all the recorded variables, age (Odds Ratio = 1.21, 95% CI 1.08; 1.35), a history of TB contact (OR = 7.31, 95% CI 2.23; 24) and the incidence of TB in the country of origin (OR = 1.01, 95% CI 1.00; 1.02) were significantly associated with a positive TST but sex (OR = 1.18, 95% CI 0.50; 2.78) and BCG vaccination status (OR = 2.97, 95% CI 0.91; 9.72) were not associated. CONCLUSIONS: TB incidence in the country of origin, BCG vaccination and age influence the TSTreaction (size or proportion of TST > or = 10 mm). However the most obvious risk factor for a positive TST is a history of contact with TB.

Adolescent↗

Reference values for methacholine reactivity (SAPALDIA study).

BACKGROUND: The distribution of airway responsiveness in a general population of non-smokers without respiratory symptoms has not been established, limiting its use in clinical and epidemiological practice. We derived reference equations depending on individual characteristics (i.e., sex, age, baseline lung function) for relevant percentiles of the methacholine two-point dose-response slope. METHODS: In a reference sample of 1567 adults of the SAPALDIA cross-sectional survey (1991), defined by excluding subjects with respiratory conditions, responsiveness during methacholine challenge was quantified by calculating the two-point dose-response slope (O'Connor). Weighted L1-regression was used to estimate reference equations for the 95th , 90th , 75th and 50th percentiles of the two-point slope. RESULTS: Reference equations for the 95th , 90th , 75th and 50th percentiles of the two-point slope were estimated using a model of the form a + b* Age + c* FEV1 + d* (FEV1)2 , where FEV1 corresponds to the pre-test (or baseline) level of FEV1. For the central half of the FEV1 distribution, we used a quadratic model to describe the dependence of methacholine slope on baseline FEV1. For the first and last quartiles of FEV1, a linear relation with FEV1 was assumed (i.e., d was set to 0). Sex was not a predictor term in this model. A negative linear association with slope was found for age. We provide an Excel file allowing calculation of the percentile of methacholine slope of a subject after introducing age--pre-test FEV1--and results of methacholine challenge of the subject. CONCLUSION: The present study provides equations for four relevant percentiles of methacholine two-point slope depending on age and baseline FEV1 as basic predictors in an adult reference population of non-obstructive and non-atopic persons. These equations may help clinicians and epidemiologists to better characterize individual or population airway responsiveness.

Age Distribution↗

Active and passive screening for tuberculosis in Vaud Canton, Switzerland.

AIM: This retrospective study compared the bacteriological and clinical presentation of tuberculosis and the outcome of treatment in immigrants notified for TB after active screening by chest X-ray at the border with other patients detected by passive screening. DESIGN: Retrospective study of all patients notified for TB in Vaud Canton in 2001 and 2002. RESULTS: In Vaud Canton 78% of the 179 patients notified for TB were foreign-born. Among 71 asylum seekers actively screened at the border, 49.3% [CI 37.4-61.2] were symptom-free vs 17.6% [CI 10.3-24.9] among 108 passively screened patients. In the passively screened group, the proportion of asymptomatic patients was 15.4% for Swiss patients, 8.6% for foreign workers, and 29.4% for other foreigners. The average duration of symptoms before diagnosis among patients with complaints was 2 months in actively screened foreign-born, compared to 2.5 months in passively screened patients (no significant difference by Wilcoxon-Mann-Whitney test). The proportion of pulmonary TB cases with positive smear or culture was 63.4% in actively screened patients vs 70.4% in passively detected cases. Among actively screened patients with bacteriological confirmation, 42.2% [CI 27.2-57.2] were asymptomatic compared to 13% [CI 5.31-20.7] for passively screened patients. Considering only smear positive patients, the proportion of symptom-free patients was 22.2% [CI 9.6-34.8] in 45 actively screened cases vs 11.7% [4.4-19.0] for 77 passive screening. Cure and treatment completion rate for new cases reached 88% for foreign workers, 83% for asylum seekers, 85% for Swiss patients, and 78% for other foreigners. CONCLUSIONS: Actively screened patients were more frequently asymptomatic than passively detected cases, even when considering only patients with bacteriological confirmation. The active screening by chest X-ray of an immigrant population with a high prevalence of tuberculosis allows the early detection and treatment of tuberculosis. This may contribute to the protection of the resident population from infection. The outcome of treatment for tuberculosis was satisfactory in all population groups.

Adult↗

Accelerated decline in lung function in smoking women with airway obstruction: SAPALDIA 2 cohort study.

BACKGROUND: The aim was to determine if effects from smoking on lung function measured over 11 years differ between men and women. METHODS: In a prospective population based cohort study (Swiss Study on Air Pollution and Lung Diseases in Adults) current smokers in 1991 (18-60 yrs) were reassessed in 2002 (n = 1792). Multiple linear regression was used to estimate effects from pack-years of cigarettes smoked to 1991 and mean packs of cigarettes smoked per day between 1991 and 2002 on change in lung volume and flows over the 11 years. RESULTS: In both sexes, packs smoked between assessments were related to lung function decline but pack-years smoked before 1991 were not. Mean annual decline in FEV1 was -10.4 mL(95%CI -15.3, -5.5) per pack per day between assessments in men and -13.8 mL(95%CI-19.5,-8.1) in women. Decline per pack per day between 1991 and 2002 was lower in women who smoked in 1991 but quit before 2002 compared to persistent smokers (-6.4 vs -11.6 mL, p = 0.05) but this was not seen in men (-14.3 vs -8.8 mL p = 0.49). Smoking related decline was accelerated in men and women with airway obstruction, particularly in women where decline in FEV1 was three fold higher in participants with FEV1/FVC<0.70 compared to other women (-39.4 vs -12.2 mL/yr per pack per day, p < 0.002). CONCLUSION: There are differences in effects from smoking on lung function between men and women. Lung function recovers faster in women quitters than in men. Women current smokers with airway obstruction experience a greater smoking related decline in lung function than men.

Adolescent↗

Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991-2003: methods and characterization of participants.

OBJECTIVES: The Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) was designed to investigate the health effects from long-term exposure to air pollution. METHODS: The health assessment at recruitment (1991) and at the first reassessment (2001-3) consisted of an interview about respiratory health, occupational and other exposures, spirometry, a methacholine bronchial challenge test, end-expiratory carbon monoxide (CO) measurement and measurement for atopy. A bio bank for DNA and blood markers was established. Heart rate variability was measured using a 24-hour ECG (Holter) in a random sample of participants aged 50 years and older. Concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3) and particulates in ambient air have been monitored in all study areas since 1991. Residential histories collected over the 11 year follow-up period coupled with GIS modelling will provide individual long-term air pollutant exposure estimates. RESULTS: Of 9651 participants examined in 1991, 8715 could be traced for the cohort study and 283 died. Basic information about health status was obtained for 8047 individuals (86% of alive persons), 6 528 individuals (70%) agreed to the health examination and 5 973 subjects (62%) completed the entire protocol. Non-participants in the reassessment were on average younger than participants and more likely to have been smokers and to have reported respiratory symptoms in the first assessment. Average weight had increased by 5.5 kg in 11 years and 28% of smokers in 1991 had quit by the time of the reassessment.

Adult↗

Passive smoking exposure among adults and the dynamics of respiratory symptoms in a prospective multicenter cohort study.

OBJECTIVES: The aim of this study was to measure the effects of past exposure to environmental tobacco smoke on the day-to-day dynamics of four respiratory-symptom classes in a diary study including adult never-smokers. METHODS: As part of SAPALDIA (Swiss study on air pollution and lung diseases in adults), a prospective multicenter cohort study, 1421 life-time adult nonsmokers were followed for 2 years with the use of daily questionnaires filled out during one to six periods of 4 weeks spread over 2 years (1992-1993). The hazard ratios (HR) of getting or losing respiratory symptoms from one day to another were determined in association with past exposure to environmental tobacco smoke. RESULTS: In a sample of adult never-smokers, an association between self-reported past exposure to environmental tobacco smoke and deteriorated average symptom dynamics was found for all of the outcomes considered, showing HR values from 1.09 to 1.21 for developing symptoms and HR values from 0.91 to 0.83 for getting rid of them. Exposure to environmental tobacco smoke, including the workplace, was negatively associated with the length of intervals without symptoms of bronchitis (HR 1.33) and asthma (HR 1.27), while exposure to environmental tobacco smoke confined to places outside work was positively associated with the length of episodes of any respiratory symptom and lower-respiratory-tract symptoms (HR 0.78-0.77). CONCLUSIONS: The results suggest that exposure to environmental tobacco smoke has adverse effects on the dynamics of respiratory symptoms, and the size (magnitude) and type of effects appear to depend on the place of exposure.

Adult↗

Five-day plan for smoking cessation using group behaviour therapy.

The "Five-Day Plan to Stop Smoking" (FDP) is an educational group technique for smoking cessation. We studied a cohort of 123 smokers (55 men, 68 women, mean age 42 years) who participated in 11 successive FDP sessions held in Switzerland between 1995 and 1998 and who were followed up for at least 12 months by telephone or direct interview. Overall, 102 of the 123 subjects (83%) had stopped smoking by the end of the FDP, and self-declared smoking cessation rate was 25% after one year. The following factors potentially associated with outcome were studied: age, sex, smoking habit duration, cigarettes per day, Fagerström Test for Nicotine Dependence (FTND), group size, and medical presence among the group leaders. Smoking habit duration was the only variable which showed a statistically significant association with success: the rate of smoking cessation was higher among patients who had smoked for less than 20 years (34.7% vs. 18.9%, p = 0.049). Stress was the most common cause of relapse. The FDP appears to be an effective smoking cessation therapy. Propositions are made in order to improve the success rate of future sessions.

Adult↗

Electronic monitoring of long-term use of the nicotine nasal spray and predictors of success in a smoking cessation program.

This study evaluated the efficacy of prolonged administration (18 months) of a nicotine nasal spray in smoking cessation and attempted to characterize the pattern of use of the nasal spray with a specially developed electronic monitor in an effort to assess the factors associated with cessation success or failure. Study participants were 92 patients in a smoking cessation unit of a medical outpatient clinic in Switzerland. Participants were daily smokers who had smoked for more than 5 years and were highly motivated to quit. The main outcome measure was the number of abstainers at 12 and 24 months. Their use of the spray was monitored using a microchip (MDILog) that recorded the date and time of every actuation. Success rates were 17.4% at 12 months and 9.8% at 24 months. During the first month of study, median use was 12 puffs/day in abstainers and 6 puffs/day in failures (p=.049). Abstainers used the spray less in the morning compared with failures (26.6% vs. 32.8% of the total median daily dose; p=.028). By contrast, abstainers used the spray more in the evening/night compared with failures (35.3% vs. 26.7% of the total median daily dose; p=.007). Abstinence during the first two weeks was associated significantly with cessation success at 6 months (OR=17.10) and 24 months (OR=11.09). Although the pattern of use of the nasal spray differed between successful quitters and failures (used in higher doses by the successful quitters), mean daily consumption during the first month was not predictive of success. Mean daily consumption of the nicotine nasal spray remained lower than expected in most participants, particularly in failures.

Administration, Inhalation↗

Outcome of treatment of pulmonary tuberculosis in Switzerland in 1996.

PRINCIPLES: Adequate treatment of pulmonary tuberculosis cures patients and reduces transmission. The study assesses treatment outcomes under current conditions in Switzerland. METHODS: Retrospective cohort study including all TB cases with positive sputum cultures notified to the national surveillance system between July 1996 and June 1997. Ten months after notification, treating physicians reported the outcomes using WHO categories. RESULTS: Of 265 patients, 209 (79%) completed at least 6 months' treatment, 3 (1%) were treatment failures, 23 (9%) died, 8 (3%) defaulted from treatment and 22 (8%) left the country. The proportion of successful treatments did not significantly differ between the 103 Swiss-born (80%) and the 162 foreign-born (78%) patients. There were 19 deaths (18%) in the Swiss-born and 4 (2%) in the foreign-born groups; death was caused by TB in two patients, 10 died of other causes (cause unknown in 11). In the foreign-born group there were 31 (19%) potentially unsatisfactory outcomes (treatment failure, default from treatment, transfer abroad) and in the Swiss-born group 2 (2%). Default from treatment involved 8 patients, 6 of whom were asylum seekers. In a multivariate analysis potentially unsatisfactory outcomes were not significantly associated with foreign origin but with status as a foreigner of irregular or unknown legal status (adj. OR 8.8; 95% CI 1.4 to 53.7). CONCLUSIONS: Overall treatment success rates are satisfactory and similar to those of other western European countries. Potentially unsatisfactory outcomes are more common in foreign-born persons of irregular legal status. Tracking of non-adherent patients by health workers could further improve outcomes.

Adolescent↗

Screening and treatment for latent tuberculosis infection among asylum seekers entering Switzerland.

AIM OF THE STUDY: To evaluate the compliance of doctors and patients with the current recommendations for screening and preventive treatment of immigrants with a positive tuberculin skin test (TST) suggestive of latent tuberculosis infection (LTBI). METHODS: Retrospective cohort study of all asylum seekers entering Switzerland between 1 January 1993 and 31 December 1993 and assigned to the cantons of Aargau, Fribourg, Geneva, Neuchâtel, Valais and Vaud, who underwent a TST at the border. The medical documents of all individuals with a TST size suggestive of LTBI (> or = 10 mm in children <15 years, > or = 18 mm in young adults aged 15-25 years) were reviewed for final diagnosis, therapeutic decision, compliance with treatment if prescribed, and notification for tuberculosis within the next 3 years. RESULTS: Among 2515 asylum seekers, 172 had a positive TST suggestive of LTBI. The documents of 93 persons were available. The final diagnosis was LTBI in 71 cases, possible tuberculosis in 10 cases, an effect of BCG immunisation in 10 cases, and other diagnoses in 2 cases. Among 82 individuals with normal chest X-ray or no radiological examination, only 37 (46%) received a preventive treatment and one a full course of antituberculosis drugs. Among 11 persons with an abnormal chest X-ray, 2 received a full course of antituberculosis drugs, 7 a preventive therapy and 2 had no treatment prescribed. Among the 44 subjects in whom a preventive treatment was prescribed, 30 adhered to the treatment regimen. One case (without prescribed treatment) was notified for tuberculosis two years after entry. CONCLUSIONS: Compliance of doctors and patients with current recommendations for examination and treatment of immigrants with a TST suggestive of LTBI is unsatisfactory. New guidelines are needed to provide a clearer definition of the indications and explain the benefits of treating LTBI.

Adolescent↗

Influence of long-term smoking reduction on health risk markers and quality of life.

We have recently published efficacy and safety data of a study using an oral nicotine inhaler in smoking reduction. The current analysis was undertaken to assess the secondary objectives of the trial: the influence of long-term smoking reduction on health risk markers. Four hundred healthy volunteers, unable or unwilling to stop smoking immediately, were enrolled in a double-blind, randomized, placebo-controlled trial in smoking reduction; 310 were evaluable up to 2 years. Participants were randomized to active or placebo inhalers as needed for up to 18 months, with subjects encouraged to reduce their smoking as much as possible; counseling took place over a 2-year period. For the current prospective cohort study, the number of daily cigarettes, carbon monoxide (CO), cotinine, cardiovascular risk factors, pulmonary function tests, and quality of life were compared between successful reducers (n = 25) and unsuccessful reducers (control group, n = 285). Success was defined as a reduction of daily cigarettes of at least 50% from week 6 to 2 years, verified by a decrease in exhaled CO at all visits compared with baseline. At 2 years, successful reducers showed a significantly greater decrease in cotinine levels (60% vs. 1%, p < 0.001), cholesterol/high-density lipoprotein (HDL) ratios (-2.42 vs. -1.67, p = 0.025), hemoglobin concentrations (-5.67 vs. -1.34 g/l, p = 0.023), pulse rate (-3.7 vs. +1.0 bpm, p = 0.043), and significantly improved general health score (9.40 vs. 2.34, p = 0.049); whereas no difference was found in forced expiratory volume during 1 s (FEV1) and forced vital capacity (FVC) compared with controls. The benefits of long-term smoking reduction of at least 50% of daily cigarettes were not offset by compensatory smoking, and the marked decrease in markers of smoke exposure had a positive influence on several cardiovascular risk markers and quality of life assessments.

Adult↗

Nicotine replacement to reduce cigarette consumption in smokers who are unwilling to quit: a randomized trial.

The objective of this study was to assess whether nicotine replacement therapy, administered in a real-life situation, could reduce cigarette consumption in smokers who were not prepared to quit smoking. Daily smokers of more than 20 cigarettes per day who had no intention to quit smoking in the next 6 months were recruited from the general population and randomly assigned to either a 6-month treatment of nicotine (choice among a 15-mg nicotine patch, a 4-mg nicotine gum, a 10-mg nicotine inhaler, or a combination of these, N = 265), matching placebo products (N = 269), or no intervention (N = 389). Products were sent to participants by mail. Education was limited to a booklet. Of 923 participants, 879 (95%) were followed up after 6 months. Mean baseline consumption was 30 cigarettes per day in all groups. At 6 months, cigarette consumption decreased by a median of 10 cigarettes per day in the nicotine group, 7.5 in the placebo group, and 2.5 among controls ( < 0.04 for all pair-wise comparisons). Smoking cessation rates were low (2%-4%) and did not differ significantly between groups. Quit attempts were less frequent among controls (21%) than among the nicotine (28%, = 0.04) and placebo (27%, = 0.08) subjects. In conclusion, nicotine replacement therapy helped smokers reduce their cigarette consumption and maintain this reduction over 6 months, but a large part of this reduction was attributable to a placebo effect. Nicotine treatment for smoking reduction had no detectable impact on smoking cessation.

Administration, Cutaneous↗