A randomized double-blind clinical trial of a mammalian cell-derived recombinant DNA hepatitis B vaccine compared with a plasma-derived vaccine.

Eight hundred volunteers from heath care and emergency fields participated in a randomized double-blind clinical trial of a new experimental mammalian cell-derived recombinant DNA hepatitis B vaccine (Betagen) compared with a licensed plasma-derived vaccine (Heptavax-B). Vaccine injections (20 micrograms) were administered intramuscularly at 0, 1, and 6 months, and sera were tested at 0, 1, 2, 3, 6, 7, and 12 months for hepatitis B surface antigen, antibody to hepatitis B surface antigen, and antibody to hepatitis B core antigen. Data from 745 vaccinees (93.1%), analyzed at the 7th month of follow-up, showed no significant difference in the seroconversion rates for Betagen (94.4%) vs Heptavax-B (97.3%), but the geometric mean titer of antibody was significantly higher for Heptavax-B (11 833 mIU/L) than for Betagen (4628 mIU/mL). The antibody response of Betagen was significantly and independently related to age and sex, while that of Heptavax-B was related to age only. Reported side effects from both vaccines were minor and mild, with approximately one fourth of all vaccinees reporting at least one side effect. Vaccinees, who had a protective level of antibody at the 7th month, were tested for antibodies at the 12th month. Of those in the Betagen-vaccinated group and those in the Heptavax-B-vaccinated group, 99.0% and 100%, respectively, were still protected. There was a proportionately larger decline in the geometric mean titers of antibody to hepatitis B surface antigen for Heptavax-B than for Betagen.

Conceptual and methodological issues regarding the epidemiology of iron deficiency and their implications for studies of the functional consequences of iron deficiency.

This paper reviews the measures of iron status (hemoglobin, hematocrit, mean corpuscular hemoglobin concentration, mean cell volume, free erythrocyte protoporphyrin, serum iron, transferrin saturation, and serum ferritin) that are potentially available for inclusion in field studies of the relationship between iron and mental performance. The characteristics of these measures (sensitivity to iron status, specificity to iron, and diurnal and day-to-day variability) are reviewed and the implications of choice of variable for the design, analysis, and interpretation of studies are discussed. Brief consideration is given to the question of confounding variables and to sources of both false-positive and false-negative conclusions. The explicit message of the paper is that there is no perfect choice of measure of iron status but, given explicit definition of the research question, there are preferred choices that can most effectively combine the choice of variable and the design of the study.

Effect of psyllium in hypercholesterolemia at two monounsaturated fatty acid intakes.

We performed two studies to determine whether the lipid-lowering effect of viscous soluble fiber was modified by monounsaturated fatty acid (MUFA). First, psyllium (1.4 g/MJ) was compared with wheat bran (control) in 1-mo metabolic diets by using a randomized crossover design (n = 32 hyperlipidemic subjects). The background diet contained approximately 6% of energy as MUFA (20% of total fat). The second study (n = 27 hyperlipidemic subjects) was similar to the first but the background diet contained approximately 12% MUFA (29% of total fat) because of the addition of canola oil. At both fat intakes, psyllium resulted in significant reductions in total, low-density-lipoprotein (LDL), and high-density-lipoprotein (HDL) cholesterol compared with the wheat bran control. For the psyllium diet at 6% compared with 12% MUFA, the decreases in LDL cholesterol were 12.3 +/- 1.5% (P < 0.001) and 15.3 +/- 2.4% (P < 0.001), respectively. With the higher-MUFA diet triacylglycerol fell significantly over the control phase (16.6 +/- 5.5%, P = 0.006) and the ratio of LDL to HDL cholesterol fell significantly over the psyllium phase (7.3 +/- 2.8%, P = 0.015). Psyllium and MUFA intakes were negatively related to the percentage change in the ratio of LDL to HDL cholesterol (r = -0.34, P = 0.019 and r = -0.44, P = 0.002, respectively). Chenodeoxycholate synthesis rate increased (30 +/- 13%, P = 0.038) with the psyllium diet in the 12 subjects in whom this was assessed. We conclude that psyllium lowered LDL- and HDL-cholesterol concentrations similarly at both MUFA intakes. However, there may be some advantage in combining soluble fiber and MUFA to reduce the ratio of LDL to HDL cholesterol.

Management of intractable ventricular tachyarrhythmias after myocardial infarction.

Twenty-five patients with recent or old myocardial infarction were studied because they had life-threatening ventricular arrhythmias that required repeated cardioversions and were intractable to medical management. All patients had had a large anterior infarction a mean of 4.6 weeks before the emergence of the arrhythmias and all had severe left ventricular dysfunction. Cardiac catheterization or autopsy revealed a left ventricular aneurysm in 18 of 18 patients and obstruction of the left anterior descending coronary artery in 20 of 20 patients. Of 16 patients treated surgically with aneurysm resection or coronary bypass grafting, or both, 10 (62 percent) were alive after 3 to 39 (mean 26) months of follow-up. The perioperative mortality rate was 31 percent and only one patient died during the postoperative follow-up period 4 months after discharge from the hospital. By contrast, all nine medically treated patients died either in the hospital (four patients) or suddenly within 2 months of discharge (five patients). Ventricular fibrillation was documented as the cause of death in five of these patients. Surgical intervention was found to improve significantly the survival of these patients (P less than 0.02). The perioperative mortality rate was lower when at least 4 weeks had elapsed from acute infarction to surgery (10 versus 67 percent) and when the procedure included coronary bypass grafting (13 versus 50 percent), although these differences were not statistically significant (P greater than 0.05).

An investigation of the association between exposure to styrene and hearing loss.

The importance of the association between advancing age and hearing loss is well recognized. Further, prolonged significant noise exposures are also known to result in permanent hearing loss. However, little is known of the contribution of industrial chemical exposures to hearing loss. Information available, from both animal and human studies, raises the possibility that certain aromatic hydrocarbons are ototoxic. The purpose of this study was to assess whether occupational styrene exposure causes hearing loss in a group of workers in the fiber-reinforced plastics manufacturing industry. The hearing acuity of 299 subjects was determined, using pure-tone screening audiometry, at the beginning of a single workshift and again at the end of the shift. On the same day, the personal, time-weighted average exposures of each subject to both styrene and noise were measured. In addition, information on the following factors was obtained from each participant: previous work history, including exposures to noise and chemicals; use of personal protective equipment for noise or solvents; personal and family history of hearing problems; and smoking history. Current exposures together with work histories were used to construct lifetime noise and styrene exposure indices. No conclusive evidence was found for a chronic styrene-induced effect on hearing acuity, when both noise and styrene lifetime exposures were taken into account. As expected, age and noise exposures were highly important variables, both positively associated with hearing loss. In addition, the detrimental effect of noise exposure on hearing acuity was found to be strengthened with increased age. Noise and styrene exposures were highly correlated, clearly illustrating the importance of considering all associated variables in analysis of such data. No evidence was found for a relationship between smoking, recreational noise, solvent exposures, and hearing loss.

Six-month double-blind, controlled trial of high dose, concentrated beclomethasone dipropionate in the treatment of severe chronic asthma.

A six-month double-blind controlled trial compared a 2,000 microgram per day dose of beclomethasone dipropionate aerosol (BDP), with current upper level doses of 800 micrograms per day of the standard BDP, in asthmatics requiring oral corticosteroids in addition to BDP and bronchodilators. Both groups showed a significant reduction in their oral steroid requirements during the study, with a 34 percent reduction in the lower dose group and a 57 percent reduction in the high dose BDP group while maintaining good symptomatic control of asthma; there was an associated improvement in baseline serum cortisol levels. Over the same period, the pulmonary function of the lower dose group showed significant worsening relative to that of the group receiving the high dose BDP which improved. There was no increase in dysphonia or oropharyngeal candidiasis among those using the concentrated BDP. We conclude that high dose concentrated BDP appears to be a safe medication in long-term steroid-dependent asthma, and is effective in reducing dependence on the use of oral corticosteroid with associated improvement both in pulmonary and adrenal function.

Effect of chest wall vibrations on pulmonary function in chronic bronchitis.

Manual chest wall vibration is one physiotherapeutic technique frequently employed in the management of respiratory disease. A clinical study was undertaken to examine the effects of manual chest wall vibrations on pulmonary function and arterial oxygen saturation in patients with chronic bronchitis. Twelve patients participated in a three-day experimental design where the factors of three different days and three different treatments were randomized and balanced. On one day, deep-breathing exercises were given; on another, deep-breathing exercises with vibrations; and on the remaining day, no treatment was given. Lung volumes were measured before and after each maneuver, and arterial oxygen saturation was monitored continuously. There was a significant decrease in the expiratory reserve volume (ERV) immediately following the deep-breathing exercises alone, which remained constant after the 15-minute rest period (p = 0.032). The remaining outcome parameters do not appear to be significantly affected. Chest wall vibrations do not decrease the ERV in patients with chronic bronchitis.

An efficacy trial of a mammalian cell-derived recombinant DNA hepatitis B vaccine in infants born to mothers positive for HBsAg, in Shanghai, China.

We conducted a randomized, double-blind clinical trial of an experimental mammalian cell-derived DNA hepatitis B vaccine (Betagen, Connaught Laboratories Ltd, Toronto, Canada) to determine its efficacy in infants born to mothers who were carriers of hepatitis B surface antigen (HBsAg). Four groups of 55 infants received injections as follows: (1) a licensed plasma-derived vaccine (Lanzhou, Lanzhou Institute for Biological Products, Lanzhou, People's Republic of China), 20 micrograms; (2) Betagen, 20 micrograms; (3) Betagen, 20 micrograms+hepatitis B immune globulin (HBIG); and (4) Betagen, 10 micrograms+HBIG. Vaccine injections were given at birth and at 1 and 6 months and HBIG was given at birth. The vaccines were compared to a historical placebo control group. The efficacy of Betagen alone was 82.6% compared to 51.0% for the Lanzhou. Efficacy of Betagen increased with the concomitant use of HBIG. No infants who were HBsAg negative at birth and/or were born to hepatitis B e antigen (HBeAg) negative mothers became carriers. The rate of HBsAg in infants receiving Betagen alone, and born to mothers who were HBeAg positive, decreased from 60% at birth to 20% by the ninth month, compared to 62.5% and 50% (respectively) for Lanzhou. The percentage of infants with protective levels of antiHBs was significantly higher for Betagen alone than for Lanzhou, but the geometric mean titre of antiHBs for responders was not significantly different. We have shown that Betagen alone is highly efficacious in preventing the development of hepatitis B in infants born to mothers who are carriers of HBsAg and is also highly effective in reducing the carriage of HBsAg in infants who are HBsAg positive at birth and/or born to HBeAg positive mothers.

PIP: Researchers assigned 220 infants born at 5 participating hospitals in Shanghai, China to receive either a 20mcg of an experimental recombinant DNA hepatitis B vaccine (Betagen), a licensed plasma derived hepatitis B vaccine (Lanzhou), 20 mcg of Betagen and hepatitis B immune globulin (HBIG), or 10mcg of Betagen and HBIG to determine the efficacy of Betagen in infants born to mothers with hepatitis B surface antigen (HBsAg) positive. Since China is a hyperendemic hepatitis B carrier area (in Shanghai, for example, prevalence rate is 57%), China hopes to reduce the carrier state via a low cost, safe, immunogenic, and efficacious recombinant vaccine. 20mcg of Betagen resulted in 82.6% efficacy which was significantly higher than that of Lanzhou (51%). The efficacy increased when HBIG was administered with the 20mcg of Betagen (92%). None of the infants born HBsAg negative and/or born to hepatitis B e antigen (HBeAg) mothers later became carriers. Further the HBsAg positive fell from 60-2-% in 9 months whereas these corresponding figures for those who received only Lanzhou were 62.5% and 50%. Even though the percentage of infants with protective levels of antiHBs stood much higher in those who received only Betagen than for those who received Lanzhou in all the months of follow up, except the 1st, their geometric mean titre of antiHBs was not statistically significant. Since Betagen prompted a quick antibody response which probably helped decrease HBsAg in the serum of those infants already positive for HBsAg at birth, it had an advantage over Lanzhou. In conclusion, Betagen given alone proved to be very efficacious in preventing hepatitis B in infants born to carriers of HBsAg. Further it was effective in reducing carriage of HBsAg in infants born HBsAg positive and/or born to HBeAg positive mothers.

A study of the reliability of the Canada Fitness Survey questionnaire.

PURPOSE: The purposes of this study are to assess the reliability of the physical activity components of the Canada Fitness Survey (CFS) questionnaire (N = 64 males, N = 63 females) and the Canadian Aerobic Fitness Test (N = 44 males, N = 52 females) in a sample of subjects between 15 and 80 yr. RESULTS: The intraclass correlation (rI) for the fitness scores was 0.98. The activity variables showed low to moderate correlations (rI = 0.48-0.53). Correlations were higher for males (rI = 0.38-0.65) than females (rI = 0.28-0.60) for most of the activity variables reported. Males generally report leisure activity more reliably than nonleisure activity, whereas the opposite was true for females. Males reported strenuous activity with higher reliability (rI = 0.86) than females (rI = 0.31). There was considerable variation in the reliability of specific activities. Of the components of physical activity (time, intensity, duration) that comprise the energy expenditure (EE) variable, the least reliably reported is intensity for both males (rI = 0.43) and females (rI = 0.55). CONCLUSIONS: The CFS questionnaire is moderately reliable for most measures of physical activity. Estimates of reliability vary considerably among the various activities and components of these activities and between males and females.

A study to validate the Canadian Aerobic Fitness Test.

Our purpose was to assess the validity of VO2 max values predicted from The Canadian Aerobic Fitness Test (CAFT) by comparing them with peak VO2 values measured during a maximal treadmill protocol. Male and female subjects, 15-69 yr (n = 129), performed two submaximal exercise tests (CAFT protocol), and one maximal treadmill test. There was no significant heart rate habituation between the first two CAFT protocols. Peak VO2 values measured during the treadmill test (TM) were significantly higher than those predicted from the CAFT whether the sample was analyzed overall or categorized by sex. When the sample was categorized by age group, all but groups 1 (15-19) and 6 (60-69) had treadmill peak VO2 values significantly higher than those predicted using Jetté's equation. Using treadmill measured peak VO2 scores as the gold standard, VO2 max predictions using the CAFT protocol and Jetté equation placed individuals of lower fitness levels more accurately than highly fit individuals, into one of five fitness categories.

Water nitrates and CNS birth defects: a population-based case-control study.

The relation between maternal exposure to nitrates in drinking water and risk of delivering an infant with a central nervous system (CNS) malformation was examined by means of a case-control study in New Brunswick, Canada. All cases of CNS defects for a "high" and a "low" prevalence area of New Brunswick, for the years 1973-1983, were included in the study. Controls were selected randomly from the livebirth files for the province, matched on county of maternal residence and date of birth. One hundred and thirty (130) cases were identified and individually matched with two controls each. Individual water samples were collected from the case and control mother's address given on the birth or stillbirth records. The study revealed that the effect of nitrate exposure in water was modified by whether the source of the drinking water was a private well or a public municipal distribution system. Compared to a baseline nitrate level of 0.1 ppm, exposure to nitrate levels of 26 ppm from private well water sources was associated with a moderate, but not statistically significant, increase in risk (risk odds ratio = 2.30; 95% confidence interval = 0.73-7.29). If the source of drinking water was a municipal distribution system or a private spring, an increase in nitrate exposure was associated with a decrease in risk of delivering a CNS-malformed infant; however, these effect estimates were not statistically significant. The positive increase in risk with nitrate exposure from well water sources requires further study using a larger case series and a larger proportion of exposures to nitrate levels exceeding 5 ppm.

Adjusting for clustering in survey research.

The current widespread application of cluster sampling in survey design presents concerns to the researcher regarding the chosen unit of study. The statistical power of a study could be spuriously increased or decreased, sample size could be altered dramatically, and the uniqueness of the individual unit under study (e.g., a patient) could be lost and substituted by average values of characteristics depending on which unit of study is selected. The 1985 National Ambulatory Medical Care Survey of the U.S. National Center for Health Statistics was used to illustrate research methodologies that would deflate spuriously high results due to clustered sampling. Using the individual patient as the study unit, correction factors ranging from 1.99 to 35.40 were calculated in order to deflate exaggerated t-tests, chi-square, and F values of predictor variables. The effect of clustering was more marked on (1) continuous rather than binary outcome variables, as the former provide a richer environment to form clusters; and (2) on outcome variables relating to the practice-related or personal style of physicians. Using the physician (who represented a cluster of patients) as the unit of study, it was realized that correction factors were relevant to physician-specific predictors but not patient-specific predictors. Using design effect correction factors developed from a simple univariate analysis of variance, pharmacoepidemiologists can analyze accurately the currently available large survey databases of clustered samples.

Pi phenotypes in North American workers: racial differences and comparisons with reported frequencies.

The distribution of Pi phenotypes among Caucasian and Asian workers in British Columbia, Canada were found to differ significantly. Among Caucasians the frequency of the M allele was 0.9428, very similar to frequencies reported in other North American Caucasian populations. Among Asians only the M allele was found, further confirming the rarity of other alleles in such populations. The distribution of phenotypes in the Caucasian population agreed with the predictions of the Hardy-Weinberg law.

Racial differences in lung function: search for proportional relationships.

A comparison of lung function in Caucasian and East Indian woodworkers revealed marked differences in FEV, FVC, AND MMF in relation to predicted age- and height-specific values of these variables reported in the literature. These findings were not attributable to differences in smoking habits, frequency of respiratory disease, or employment characteristics. Rather, they suggested that the standard values employed were inappropriate for East Indians. An attempt was made to confirm previously reported suggestions of consistent proportional differences in lung function between racial groups which would permit the calculation of a single correction factor. Evidence of a consistent proportional relationship was found for FEV over a wide range of heights and for FVC over a limited range of heights. However, no such relationship was found for MMF.

Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.

OBJECTIVE: To estimate the incidence of serious and fatal adverse drug reactions (ADR) in hospital patients. DATA SOURCES: Four electronic databases were searched from 1966 to 1996. STUDY SELECTION: Of 153, we selected 39 prospective studies from US hospitals. DATA EXTRACTION: Data extracted independently by 2 investigators were analyzed by a random-effects model. To obtain the overall incidence of ADRs in hospitalized patients, we combined the incidence of ADRs occurring while in the hospital plus the incidence of ADRs causing admission to hospital. We excluded errors in drug administration, noncompliance, overdose, drug abuse, therapeutic failures, and possible ADRs. Serious ADRs were defined as those that required hospitalization, were permanently disabling, or resulted in death. DATA SYNTHESIS: The overall incidence of serious ADRs was 6.7% (95% confidence interval [CI], 5.2%-8.2%) and of fatal ADRs was 0.32% (95% CI, 0.23%-0.41%) of hospitalized patients. We estimated that in 1994 overall 2216000 (1721000-2711000) hospitalized patients had serious ADRs and 106000 (76000-137000) had fatal ADRs, making these reactions between the fourth and sixth leading cause of death. CONCLUSIONS: The incidence of serious and fatal ADRs in US hospitals was found to be extremely high. While our results must be viewed with circumspection because of heterogeneity among studies and small biases in the samples, these data nevertheless suggest that ADRs represent an important clinical issue.

Alcohol consumption and blood pressure: analysis of data from the Canada Health Survey.

Recent epidemiologic studies report a significant association between alcohol consumption and elevations in both systolic (SBP) and diastolic (DBP) blood pressures. To test this hypothesis, we conducted a multivariate analysis of physical examination and other data on 721 men and 697 women aged 20 or more collected during the Canada Health Survey in 1978-1979. SBP and DBP were considered as separate dependent variables in multiple regression models with the following independent variables: age, alcohol consumption (measured as a 7-day recall history and as an average frequency of consumption), serum cholesterol, plasma glucose, physical activity, Quetelet index, parental history of hypertension, cigarette consumption, income, education, and exogenous hormonal use in women. In both weighted and unweighted multiple regression analyses, we could not demonstrate for either sex, a significant association between alcohol consumption (as recorded and following quadratic and logarithmic transformations) and either SBP or DBP. For both sexes, only age and Quetelet index were highly significantly (P less than 0.0001) and consistently associated with both SBP and DBP. No other independent variables were consistently associated, for either sex, with SBP and DBP. Further, the dose-response patterns noted by other investigators suggesting either a positive and linear relationship or a curvilinear relationship were not found in either our univariate or multivariate analyses. Rather, the alcohol-blood pressure curves showed no consistent patterns of any kind in either sex. These findings do not support recent claims that alcohol consumption is a determinant of elevations in either SBP or DBP.