John Wlodarczyk

Air pollution and Hospital admissions in Sydney, Australia, 1990 to 1994

OBJECTIVES This study examined the effects of outdoor air pollutants on daily hospital admissions in Sydney, Australia. METHODS A time-series analysis of counts of daily hospital admissions and outdoor air pollutants (1990 to 1994) was performed, by means of Poisson regression that allowed for overdispersion and autocorrelation. RESULTS An increase in daily maximum 1-hour concentration of nitrogen dioxide from the 10th to the 90th percentile was associated with an increase of 5.29% (95% confidence interval = 1.07, 9.68) in childhood asthma admissions and 4.60%(-0.17,9.61) in chronic obstructive pulmonary disease (COPD) admissions. A similar increase in daily maximum 1-hour particulate concentration was associated with an increase of 3.01% (-0.38, 6.52) in COPD admissions. An increase from the 10th to the 90th percentile in daily maximum 1-hour nitrogen dioxide, daily maximum 1-hour ozone, and daily mean particulate was associated with an increase in heart disease admissions among those 65 years and older of 6.71% (4.25, 9.23), 2.45% (-0.37, 5.35), and 2.82% (0.90, 4.77), respectively. Heart disease and childhood asthma were primarily associated with nitrogen dioxide; COPD was associated with both nitrogen dioxide and particulates. CONCLUSIONS Current levels of air pollution in Sydney are associated with increased hospitalization for respiratory and heart disease.

Safety and Efficacy of a Testosterone Metered-Dose Transdermal Spray for Treating Decreased Sexual Satisfaction in Premenopausal Women: A Randomized Trial

Context Testosterone levels in women gradually decline with age, and supplemental testosterone may improve sexual satisfaction in postmenopausal women. Contribution Sexually active women age 35 to 45 years with low serum free testosterone levels and low sexuality scores were randomly assigned to placebo or 3 doses of transdermal testosterone for 16 weeks. Sexually satisfying encounters increased in all 4 groups. Compared with placebo, the number increased by 0.8 per month with the intermediate dose (P = 0.04) but not with the other doses. Caution The study was too brief to measure adverse events reliably. Implication We need more evidence before prescribing testosterone supplementation to premenopausal women in clinical practice. The Editors Testosterone levels in women decline with age from the midreproductive years (1, 2) and do not change during menopause (2, 3 ). Testosterone therapy seems to improve sexual well-being in postmenopausal women (49), but few comparable data are available for premenopausal women. Women with low testosterone levels after menopause probably had low levels before menopause (3), and sexual well-being before menopause is a strong predictor of postmenopausal sexual well-being (10). These findings suggest that testosterone therapy may benefit women presenting with low libido in their late reproductive years. Premenopausal women often report decreased sexual interest, arousal, and pleasure (11, 12), yet they have few treatment options. In a randomized, placebo-controlled, crossover trial, testosterone administered as a transdermal cream improved sexual function and well-being in premenopausal women with low libido and low testosterone levels (13). However, the study enrolled few patients, efficacy was based on a 30-day recall rather than a daily event diary, and the women took only 1 dose of testosterone. We sought to determine the efficacy and safety of several doses of testosterone, administered transdermally by a metered-dose spray system, in increasing self-reported sexual satisfaction among premenopausal women who had decreased sexual satisfaction. Methods Participants We recruited potential participants by using radio and published press advertisements, and we screened them by telephone for suitability. Enrollment was from September 2003 to May 2004. The inclusion criteria were age 35 to 45 years, premenopausal status (regular menstrual cycles and follicle-stimulating hormone level <40 IU/L), body mass index (BMI) between 18 and 32 kg/m2, sexual activity (1 sexual event per 28 days, alone or with a partner) but with a low sexuality score (Sabbatsberg Sexual Self-Rating Scale [14] score <42), no evidence of severe clinical depression on the Beck Depression Inventory (score <28) (15), and early-morning serum free testosterone levels of 3.8 pmol/L or less (1.1 pg/mL). In addition, each woman had to have experienced a decrease in satisfactory sexual activity of sufficient concern to seek medical advice or treatment and answer yes to each of the following questions: In previous years did you find sexual activity satisfying? Has there been a decline in your satisfaction with sexual activity? Would you like to use a hormonal treatment that may improve the level of satisfying sexual activity? All volunteers had general good health on history and physical examination and had had a Papanicolaou smear within the past year. Volunteers had to have had 3 satisfactory sexual events (SSEs) at most over 28 days at baseline (week 0) and, if in an established relationship, their partner present at least 50% of the time. We excluded women who were planning a pregnancy or were breastfeeding; had relationship problems, poor feelings for their partner, or dyspareunia; had received pharmacotherapy for depression within 8 weeks of screening or were taking medication known to interfere with normal sexual function (such as -blockers and -blockers); or had ever used androgen therapy. We also excluded women with a history of acne or hirsutism or treatment with antiandrogens for hirsutism in the previous 5 years, past cancer other than nonmelanotic skin cancer, uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg), any major chronic major illness that would impair overall health and well-being, genital bleeding of unknown cause, intake of more than 3 standard alcoholic drinks per day or addictions to any drugs or medication within the past 5 years, and use of medications known to interfere with sex steroid metabolism. The use of thyroid hormone was acceptable if the dose was expected to remain stable throughout the study. The protocol required all participants to use a medically acceptable form of contraception, including oral contraceptive pills, and to have a negative pregnancy test result at screening. All women gave voluntary, written informed consent and were specifically advised that the effects of the study doses of testosterone in the setting of pregnancy or breast-feeding were unknown. We stressed the necessity of contraception, and all participants received contraceptive counseling. Women who declined contraception were excluded. We obtained study approval from the human research and ethics committee at each institution. The study met the Clinical Trial Notification requirement of the Therapeutic Goods Administration of Australia and the requirements for an Investigational New Drug Application for the U.S. Food and Drug Administration. Design The study was a multicenter, randomized, double-blind, placebo-controlled trial. Eligible patients were first asked to complete a 4-week diary to characterize baseline sexual function. We invited women who met the eligibility criteria for baseline sexual activity to enter the placebo-controlled treatment stage of 16 weeks followed by 4 further weeks after therapy was discontinued. Treatments Participants were randomly assigned to receive 1 of 3 different doses of testosterone or placebo. The formulation (50 g of testosterone per L) was constant for each active dose, and the dose varied by applying different amounts of formulation with a metered-dose spray (Acrux Limited, West Melbourne, Victoria, Australia) (16). On the basis of previous pharmacokinetic studies, the highest dose (two 90-L sprays) should have increased mean serum free testosterone levels to approximately the 75th percentile of the normal range for premenopausal women (17.3 pmol/L [5.0 pg/mL]). The normal range is 3.8 pmol/L (1.1 pg/mL) to 21.84 pmol/L (6.3 pg/mL). The other study groups received half (one 90-L spray) and one third (one 56-L spray) of the highest dose of testosterone or placebo. Participants randomly assigned to placebo were further randomly assigned to 1 of 3 placebo subgroups (one 90-L spray, two 90-L sprays, or one 56-L spray) that corresponded with the 3 active treatment groups. Because findings were similar in the 3 placebo subgroups, we combined them into 1 group in the analysis. Doses were applied topically to the abdomen once a day for 16 weeks. One multidose applicator was dispensed every 4 weeks. Randomization Computer-generated randomization schedules for each center were created in blocks of 12 without stratification. The study statistician (who was not otherwise involved in the conduct of the study) generated and held the randomization schedules. The randomization sequence was generated by using the Ranuni function (SAS software, SAS Institute, Cary, North Carolina). Each unique code number in the schedule referred to a randomly allocated treatment: either a specific dose of testosterone or 1 of the 3 placebo groups. At each center, the study staff sequentially assigned participants as they became eligible to the next unassigned treatment code on the list and then identified the treatment assignment corresponding to the code number. Both participants and center staff remained blinded to treatment assignment throughout the study. Outcome Measures The primary end point (the frequency of SSEs) was recorded in the 28-day patient diary, which was completed daily and collected at week 16. Secondary end points were the frequency of SSEs recorded in the 28-day patient diaries collected at weeks 4, 8, 12, and 20; frequency of total sexual events at weeks 4, 8, 12, 16, and 20; and mean (over each 28-day evaluation period) composite and subscale scores for the Sabbatsberg Sexual Self-Rating Scale (Appendix Figure) and Psychological General Well-Being Index. The Sabbatsberg Sexual Self-Rating Scale (17) is a multiple-choice questionnaire covering 7 aspects of sexuality: sexual interest, sexual activity, satisfaction of sexual life, experience of sexual pleasure, sexual fantasy, orgasm capacity, and sexual relevancy. This scale has been validated in premenopausal women (14). The range of possible composite scores was 0 (low) to 56 (high). The Psychological General Well-Being Index (18) is a validated, 22-item multiple-choice questionnaire with subscales for anxiety, depressed mood, positive well-being, self-confidence, general health, and vitality. The range of possible composite scores is 0 (most negative affective experience) to 110 (most positive affective experience). Patients self-administered questionnaires at screening; baseline (week 0); and weeks 8, 16, and 20. The Appendix provides details of biological measurements. Appendix Figure. Sabbatsberg Sexual Self-Rating Scale. Reproduced with permission from Acta Obstet Gynecol Scand Suppl. 1977;64:1-91. Safety Assessments We compared the rates of adverse events in the 3 treatment groups with rates in the placebo group. We monitored specific known androgenic side effects, including hirsutism, by using the FerrimanGallwey scale (19) and acne by using the Palatsi scale (20), and we asked participants about voice changes at each visit after baseline. All events known to be consequences of excessive androgen use were classified as treatment-related, and all others were classified

Evaluation of a new asthma questionnaire.

The new International Union Against Tuberculosis (IUAT) bronchial symptoms questionnaire was completed by 827 subjects participating in a prospective study of respiratory symptoms and lung function in aluminum smelter workers. A modified Medical Research Council (MRC) questionnaire was also administered. Bronchial reactivity (BR) was measured in 809 subjects by methacholine challenge using a rapid method. Factor analysis demonstrated sensible clustering of responses to items unique to the new questionnaire such as nocturnal, spontaneous, and postexertional dyspnea, dust-induced dyspnea and tightness, and breathing difficulty. Responses to IUAT questions concerning past asthma, wheeze, chest tightness, morning cough and sputum, and asthma medication agreed well with corresponding items from the MRC questionnaire. Questions concerning asthma, medication, dust-induced, nocturnal, and spontaneous dyspnea, chest tightness, wheeze, nocturnal cough, postexertional dyspnea and breathing difficulty also had high validity against the criterion of concurrently measured bronchial reactivity. It is concluded that the IUAT questionnaire is a valid asthma questionnaire.

Air pollution and daily mortality in Sydney, Australia, 1989 through 1993.

OBJECTIVES This study examined the effects of outdoor air pollutants in Sydney, Australia, on daily mortality. METHODS Time-series analysis was performed on counts of daily mortality and major outdoor air pollutants (particulates, ozone, and nitrogen dioxide) in Sydney (1989 to 1993) with adjustment for seasonal and cyclical factors. Poisson regression was calculated with allowance for overdispersion and autocorrelation. The effects of lagging exposure by 0 to 2 days were assessed with single- and multiple-pollutant models. RESULTS An increase in daily mean particulate concentration from the 10th to the 90th centile was associated with an increase of 2.63% (95% confidence interval 0.87 to 4.41) in all-cause mortality and 2.68% (0.25 to 5.16) in cardiovascular mortality. An increase in daily maximum 1-hour ozone concentration from the 10th to the 90th centile was associated with an increase of 2.04% (0.37 to 3.73) in all-cause mortality and 2.52% (-0.25 to 5.38) in cardiovascular mortality. An increase in the daily mean nitrogen dioxide concentration from the 10th to the 90th centile was associated with an increase of 7.71% (-0.34 to 16.40) in respiratory mortality. Multiple-pollutant models suggest that the effects of particulates and ozone on all-cause and cardiovascular mortality, and of nitrogen dioxide on respiratory mortality, are independent of the effects of the other pollutants. CONCLUSIONS Current levels of air pollution in Sydney are associated with daily mortality.

Using Quality-Control Analysis of Peak Expiratory Flow Recordings To Guide Therapy for Asthma

International consensus guidelines [1-4] recommend that patients with asthma be given written instructions that detail when and how to increase treatment during an exacerbation of asthma [an action plan]. The purpose of an action plan is to allow the early recognition and treatment of an asthma exacerbation by the patient, thereby avoiding treatment delays and minimizing the severity of the exacerbation. The two essential components of an action plan are 1) an action point that indicates when to increase treatment and 2) an action treatment instruction that indicates how to increase treatment [5]. Action plans have received little controlled evaluation. The action treatment instruction can be evaluated by a randomized, controlled trial of treatment. For instance, several studies [1, 2] have established a role for increased corticosteroid therapy during an exacerbation of asthma. The evaluation of action points has received little attention [6]. Action points should enable the patient to detect asthma exacerbations reliably and accurately: If an action plan performs poorly, it may delay treatment. Delay in using corticosteroid therapy for an exacerbation of asthma is a feature common to severe and fatal exacerbations [7, 8]. Alternatively, an action point may falsely detect an exacerbation (a false-positive result) and lead to unnecessary therapy. The published recommendations for action points vary widely. For example, the action point recommended in the International Guidelines [2] is a peak expiratory flow value less than 80% of the patients best peak flow. In contrast, other guidelines recommend using values less than 60%, 70%, or 90% of a patients best peak flow or predicted peak expiratory flow [6, 9, 10]. It is unclear which of these action points is most appropriate for the detection of an asthma exacerbation. It is also unclear whether the same action point applies equally well to all patients or whether action points should be individualized for particular patients. Intuitively, individualized action points seem better, but ways of defining these points have received little attention. We reasoned that an action point can be viewed as a diagnostic test, the aim of which is to detect or diagnose an exacerbation of asthma. The relative value of an action point can be assessed by its ability to accurately predict such an exacerbation. We examined the operating characteristics of action points in adults who developed spontaneous exacerbations of asthma. In addition to evaluating published action points, we applied the techniques of quality control analysis to peak expiratory flow records to estimate an individualized and statistically valid action point for each patient. We hypothesized that this would be a more sensitive and specific approach to the detection of asthma exacerbations. Methods The data for analysis were collected from patients attending an asthma management and education program. Adult patients with asthma who were enrolled in the John Hunter Hospital Asthma Management Service and who kept peak expiratory flow diaries were eligible for entry into the study. The Asthma Management Service is a standardized education and management program that is offered to adults who have had an emergency presentation to the hospital with asthma. Patients are seen in an ambulatory care setting four to five times in a 3-month period. The program involves visits with a respiratory physician and a nurse educator. Its aims are to optimize asthma control; to provide instruction in asthma management skills, such as inhaler technique; to improve knowledge of asthma and asthma medication; and to instruct patients in the self-monitoring of symptoms and peak expiratory flow. Patients used a mini-Wright peak expiratory flow meter (Clement Clarke International, United Kingdom) and recorded the best of three values obtained before and 15 minutes after inhaled bronchodilator therapy in the morning and in the evening. Values were recorded in a daily diary, which was reviewed at clinic visits and collected when the patient was discharged from the Asthma Management Service. Between scheduled visits, if symptoms worsened, patients could contact a nurse educator to obtain an earlier physician review appointment. At the completion of the program, action plans were written for the patients and the patients were discharged back into the care of the physician who had referred them to the program. The records of 150 patients registered in the Asthma Management Service were screened for exacerbations of asthma. Exacerbations were defined as new medication courses of increased corticosteroid therapy (oral or high-dose inhaled corticosteroid). These courses were prescribed after assessment by a respiratory physician and used for deteriorating asthma as reflected by an increase in asthma symptoms, an increase in 2-agonist requirements, and a decrease in lung function. Forty-three exacerbations were identified in 35 patients. Diary data were extracted for three time periods: an exacerbation period, a baseline period, and a pre-exacerbation period. The 3-day exacerbation period comprised the day before a corticosteroid course was started, the day it was started, and the day after it was started. A stable baseline period was identified after a scheduled clinic visit that occurred more than 6 weeks after hospital discharge and at which therapy was not altered. Diary data for the 8 to 10 days after this visit were used as baseline data. A preexacerbation period was defined as the 7-day period immediately before the exacerbation period. Patient demographic characteristics, treatment details, and diary data were extracted using standardized forms and entered into a computerized database. Predicted peak expiratory flow values were taken from published guidelines [3]. The best peak expiratory flow for an individual person was the highest peak flow recorded in the persons diary during the stable baseline period. Statistical Analysis Quality-control analysis was done using the statistical process control procedures in Minitab statistical software, release 8 (State College, Pennsylvania). Control charts were used to study variations in peak expiratory flow over time. A summary statistic, such as the mean peak expiratory flow, was calculated for each sample (day) and plotted over time (in days). Three lines were drawn on the chart: the center line, which was an estimate of the average value of the summary statistic; a lower control limit, which was drawn 3 standard deviations below the center line; and a third line, which was drawn 2 standard deviations below the center line. If a process is in control it is very unlikely (< 3 in a 100 chance) that a point will fall outside the lower control limit. In this study, we used the lower control limit to define significant decreases in peak expiratory flow. Standard quality-control tests were used to identify deviations in the control charts. A single point falling below the lower control limit indicated that a change may have occurred (special cause) and that investigation was needed (test 1). Two other standard tests were used. Test 2 was reached when 2 of 3 points occurred in a row in a zone between 2 and 3 standard deviations from the center line. Test 3 was reached when four of five points in a row fell between 1 and 2 standard deviations from the center line or beyond (Figure 1). Figure 1. An example of a quality-control chart (x-bar chart) of peak expiratory flow recordings from a patient with asthma. Action points were obtained from published literature and from quality-control analysis. The published action points that were evaluated included a peak expiratory flow of less than 80% of predicted peak expiratory flow; a peak expiratory flow of less than 80% of a patients best peak flow; a peak flow of less than 60% of predicted peak expiratory flow; a peak flow of less than 60% of a patients best peak flow; nocturnal waking because of asthma; and use of 2-agonist therapy more than four times a day. Three tests for special causes were used to define action points from quality-control analysis and were separately applied to peak flow before and after bronchodilator therapy. An action point was defined as a success if it was reached by the patient during the exacerbation period. An action point was defined as a failure if it was reached during the baseline period or if it was not reached during an exacerbation. The successes and failures were totaled for the study group. The success rate is similar to the sensitivity of a diagnostic test. The failure rate from each action point during the baseline period is similar to the false-positive rate, and its complement is specificity. The McNemar test was used to compare the overall error rate (successes and failures) of two published action points (peak flow less than 60% of that predicted and peak flow less than 80% of that predicted) with the overall error rate from quality-control analysis, test 2. The significance level was P < 0.05. Results Thirty-five patients had a total of 43 asthma exacerbations (Table 1). Two patients required hospitalization for their exacerbations. Most patients (69%) received oral prednisolone for management (mean dose, 40 14 mg; mode, 50 mg). Each patient also received increased aerosol bronchodilator therapy. High-dose inhaled corticosteroid therapy was given to 94% of patients and was continued for as long as 14 days. The average dose of inhaled corticosteroid used during the exacerbations was 3.9 1.9 mg of either beclomethasone dipropionate (through pressurized metered-dose inhaler and valved holding chamber) or budesonide (through Turbuhaler [Astra Pharmaceuticals, North Ryde, Australia], a dry-powder metered-dose inhaler). Table 1. Patient Characteristics The performance characteristics of the action points are shown in Table 2 and Figure 2. The action points from published guidelines had varying success rates. An ac

Comparison of family history measures used to identify high risk of coronary Heart disease

We examined 15 published continuous family history measures (scores) as well as two new formulations in terms of several desirable properties. We applied the scores to sample pedigrees and found that some systematically increase with family size. In contrast to aggregate scores, non‐aggregate scores are sensitive to the age, sex, and covariate status of individual relatives but are unstable when the families are small. We also applied these scores to our own population case‐control data, characterised by a high proportion of missing and false‐negative responses. In these small families, all scores provided significant discrimination between CHD cases and controls beyond the usual categorical definition of positive family history, but appeared no better than detailed categorical definitions or even simple counts. Our new formulations offer no solution to the problems of few data; most scores apply asymptotic approximations to differences between observed and expected number of affected relatives and are not suited to small families. All scores would be improved by ruling out families with only one affected relative, as is being done in the NHLBI Family Heart Study. We recommend that researchers, when using a family history measure, consider the number of informative families and other characteristics of their data prior to choosing any particular formulation. Genet. Epidemiol. 16:344–355, 1999.

A clinical evaluation in children of the Pharmacia ImmunoCAP system for inhalant allergens

Background The Pharmacia ImmunoCAP system (CAP) for assaying serum IgE specific antibodies was evaluated in a clinical setting against skin‐prick test (SPT) perfonncd using Dome/Hollister‐Steir allergen extracts. The five cotnmon inhalant allergens D. pteronyssinus. D. farinae, mould mix, grass mix and cat epithelium were tested concurrently by both methods in 167 children aged 7.5–12 years. The specific SPT for D. pteronyssinus and D. farinae were also tested against the CAP house dust mite (HDM) mix.

Impact of inhaled corticosteroids on cortisol suppression in adults with asthma: a quantitative review

BACKGROUND Studies examining the effects of inhaled corticosteroids (ICSs) on cortisol suppression show inconsistent results, and there is uncertainty regarding the dose-response relationship between ICSs and cortisol suppression. OBJECTIVE To determine, using meta-analysis, the extent of cortisol suppression after administration of clinically relevant ICS doses in adults with asthma. METHODS Database searches (MEDLINE, EMBASE, and The Cochrane Library) using appropriate indexed terms were performed to identify eligible articles for review. Articles reporting the effects of ICSs on cortisol levels in asthmatic adults, measured using the cumulative serum or plasma cortisol, morning serum or plasma cortisol, or cumulative overnight urinary free cortisol method, were identified. All available cortisol measurements were extracted. Cortisol suppression was estimated, and treatment arms were grouped into low-, medium-, and high-dose ranges according to the Global Initiative for Asthma guidelines. A multivariate model was used to determine relationships between ICS dose and cortisol suppression and to explore sources of heterogeneity among trials. RESULTS Thirty-one studies providing information on 216 measures of cortisol suppression were included in this meta-analysis. Cortisol suppression in the low-, medium-, and high-dose groups were estimated to be 17.92% (95% confidence interval [CI], 11.08%-24.77%), 26.55% (95% CI, 17.29%-35.80%), and 36.31% (95% CI, 26.48%-46.13%), respectively. CONCLUSIONS Statistically significant cortisol suppression was evident at low doses of ICSs and increased with dose. These results support an impact of all ICSs on endogenous cortisol levels and underscore the importance of titrating ICS doses to the minimum required to maintain symptom control.

Nasal inflammation and chronic ear disease in Australian Aboriginal children

Objective: Chronic middle ear disease is common in Aboriginal children, and may be linked to nasal inflammation and Eustachian tube dysfunction. The pattern of nasal inflammation is unknown. The study reported here was performed to define the role of allergy and infection in causing nasal inflammation in Aboriginal children with chronic middle ear disease.

Exercise, Stress and Mucosal Immunity in Elite Swimmers

Elite athletes have been reported to be susceptible to upper respiratory tract infections (URTI), particularly during the period immediately prior to major competitions.1 Studies of the effects of exercise on immune parameters have shown that alterations in systemic immunity and cytokine levels are related to the intensity of the exercise and fitness of the athlete.2 In elite athletes decreases in salivary IgA levels have been observed following intense endurance exercise3,4 but it is not clear whether the changes are associated with an increased incidence of URTI.5 Psychological stress has also been shown to decrease salivary IgA levels,6 but the relevance of this observation to the immune fitness following fatiguing exercise is unclear. This prospective study assessed the impact of long term exercise (physical stress) and psychological stress on systemic and mucosal immunity and the relationship to URTI in a cohort of elite swimmers.