Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium.

BACKGROUND: Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time-risk relationship are unclear, and there is limited information on the role of antidiabetic medications. PATIENTS AND METHODS: We analyzed individual-level data from 15 case-control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates. RESULTS: Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72-2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03-1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14-0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75-8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53-1.70, for ≥15 years). CONCLUSION: This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration-risk relationship.

Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Peptic ulcer and its treatments have been associated to pancreatic cancer risk, although the evidence is inconsistent. METHODS: We pooled 10 case-control studies within the Pancreatic Cancer Case-control Consortium (PanC4), including 4717 pancreatic cancer cases and 9374 controls, and estimated summary odds ratios (OR) using multivariable logistic regression models. RESULTS: The OR for pancreatic cancer was 1.10 [95% confidence interval (CI) 0.98-1.23] for history of ulcer (OR = 1.08 for gastric and 0.97 for duodenal ulcer). The association was stronger for a diagnosis within 2 years before cancer diagnosis (OR = 2.43 for peptic, 1.75 for gastric, and 1.98 for duodenal ulcer). The OR was 1.53 (95% CI 1.15-2.03) for history of gastrectomy; however, the excess risk was limited to a gastrectomy within 2 years before cancer diagnosis (OR = 6.18, 95% CI 1.82-20.96), while no significant increased risk was observed for longer time since gastrectomy. No associations were observed for pharmacological treatments for ulcer, such as antacids, H2-receptor antagonists, or proton-pump inhibitors. CONCLUSIONS: This uniquely large collaborative study does not support the hypothesis that peptic ulcer and its treatment materially affect pancreatic cancer risk. The increased risk for short-term history of ulcer and gastrectomy suggests that any such association is due to increased cancer surveillance.

Hypnosis antenatal training for childbirth: a randomised controlled trial.

OBJECTIVE: To determine the use of pharmacologic analgesia during childbirth when antenatal hypnosis is added to standard care. DESIGN: Randomised controlled clinical trial, conducted from December 2005 to December 2010. SETTING: The largest tertiary referral centre for maternity care in South Australia. POPULATION: A cohort of 448 women at >34 weeks of gestation, with a singleton pregnancy and cephalic presentation, planning a vaginal birth. Exclusions were: the need for an interpreter; pre-existing pain; psychiatric illness; younger than 18 years; and previous experience of hypnosis for childbirth. METHODS: All participants received usual care. The group of women termed Hypnosis + CD (hypnotherapist guided) were offered three antenatal live hypnosis sessions plus each session's corresponding audio CD for further practise, as well as a final fourth CD to listen to during labour. The group of women termed CD only (nurse administered) were played the same antenatal hypnosis CDs as group 1, but did not receive live hypnosis training. The control group participants were given no additional intervention or CDs. MAIN OUTCOME MEASURE: Use of pharmacological analgesia during labour and childbirth. RESULTS: No difference in the use of pharmacological analgesia during labour and childbirth was found comparing hypnosis + CD with control (81.2 versus 76.2%; relative risk, RR 1.07; 95% confidence interval, 95% CI 0.95-1.20), or comparing CD only with control (76.9 versus 76.2%, RR 1.01, 95% CI 0.89-1.15). CONCLUSIONS: Antenatal group hypnosis using the Hypnosis Antenatal Training for Childbirth (HATCh) intervention in late pregnancy does not reduce the use of pharmacological analgesia during labour and childbirth.

Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment.

AIM: The aim of the study is to compare the effects of metformin and insulin treatment for gestational diabetes mellitus (GDM) on vitamin B12 and homocysteine (Hcy) status. METHODS: Women with GDM, who met criteria for insulin treatment, were randomly assigned to metformin (n = 89) or insulin (n = 91) in the Adelaide cohort of the metformin in gestational diabetes (MiG) trial. Fasting serum total vitamin B12 (TB12), holotranscobalamin (HoloTC), a marker of functional B12 status and plasma Hcy concentrations were measured at 20-34 weeks (at randomization) and 36 weeks gestation, then at 6-8 weeks postpartum. RESULTS: Circulating TB12, HoloTC and Hcy were similar in both treatment groups at each time point. Women who were taking dietary folate supplements at randomization had higher serum TB12 and HoloTC at randomization than those not taking folate. Overall, serum TB12 fell more between randomization and 36 weeks gestation in the metformin group than in the insulin group (metformin: -19.7 ± 4.7 pmol/l, insulin: -6.4 ± 3.6 pmol/l, p = 0.004). The decrease in serum TB12 during treatment was greater with increasing treatment duration in metformin-treated (p < 0.001), but not in insulin-treated women. CONCLUSIONS: Total, but not bioavailable, vitamin B12 stores were depleted during pregnancy to a greater extent in metformin-treated than in insulin-treated women with GDM, but neither analyte differed between groups at any stage. This adds further evidence supporting metformin as a safe alternative treatment to insulin in GDM. Further investigation is needed to evaluate whether women treated with metformin for longer periods in pregnancy require additional B12 or other supplementation.

Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved. METHODS: To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case-control studies (5585 cases and 11,827 controls) participating in the International Pancreatic Cancer Case-Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models. RESULTS: Compared with abstainers and occasional drinkers (< 1 drink per day), we observed no association for light-to-moderate alcohol consumption (≤ 4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2-2.2 for subjects drinking ≥ 9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area. CONCLUSION: This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.

Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4).

BACKGROUND: To evaluate the dose-response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables. METHODS: We analyzed data from 12 case-control studies within the International Pancreatic Cancer Case-Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models. RESULTS: Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0-1.3) for former smokers and 2.2 (95% CI 1.7-2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR=3.4 for ≥35 cigarettes per day, P for trend<0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR=2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years. CONCLUSIONS: This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.

Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco. MATERIALS AND METHODS: We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case-control studies (6056 cases and 11,338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates. RESULTS: Compared with never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2-2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4-1.6). The OR was 1.1 (95% CI 0.69-1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for ≥ 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75-1.3). CONCLUSION: This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use.

Interobserver variability in the measurement of fetal middle cerebral artery peak systolic velocity in a tertiary fetal medicine unit.

OBJECTIVES: To investigate the interobserver variability of fetal middle cerebral artery (MCA) peak systolic velocity (PSV) Doppler measurements in a tertiary fetal medicine unit. METHODS: This was a prospective cohort study of pregnant women between 22 and 34 weeks of gestation who underwent fetal MCA-PSV Doppler velocimetry by a paired combination of operators. A set protocol was followed; ease of scanning was recorded and three quality assurance parameters were analyzed. The interobserver variability was determined. In addition, individual operator characteristics were determined by analyzing the variation of each operator relative to all his/her paired colleagues, and their quality assurance parameters. RESULTS: Two hundred and eighty-five women had completed paired fetal MCA-PSV Doppler measurements. Eighty-three (29%) of the ultrasound examinations requested were for suspected fetal anemia and 202 (71%) were for other obstetric indications. The interobserver variation was less than 10% in 78% of the paired MCA-PSV Doppler measurements whereas 99% had less than 15% variation. The intraclass correlation coefficient of each operator when compared with all his/her colleagues ranged from 0.82 to 0.95. The overall mean variability of the MCA-PSV recorded by a given operator, relative to all his/her paired colleagues, ranged from + 5.26% to - 6.47% in all but one operator whose value was + 13.5% (standard deviation factor, 1.13-1.22). Logistic regression analysis, using a 10% or greater variation in MCA-PSV as a binary outcome variable, showed a significant difference when inappropriate angle correction was detected (P < 0.001). CONCLUSIONS: Clinically acceptable interobserver variability was obtained in fetal MCA-PSV Doppler measurements. Inappropriate angle correction was found to be a significant predictive factor for increased interobserver variability. Analysis of mean variation identified operators who were outliers enabling quality assurance within the unit.

Consumption of untreated tank rainwater and gastroenteritis among young children in South Australia.

BACKGROUND: Tank rainwater is a source of untreated drinking water in Australia and elsewhere. The aim of this study was to determine whether the risk of gastroenteritis among children who drank tank rainwater differed from that of children who drank treated public mains water. METHODS: A cohort study of 1,016 4- to 6-year old children who drank rainwater or treated mains water in rural South Australia was undertaken in 1999. Parents kept a daily diary of their child's gastrointestinal symptoms and water consumption for a period of 6 weeks. Data on respiratory illness and other risk factors for gastroenteritis were also collected. RESULTS: The incidence of gastroenteritis among children was 3.8-5.3 episodes per child-year, but most episodes (60%) lasted just 1 day. No increase in odds of gastroenteritis was observed among children who drank rainwater compared with treated mains water. The adjusted odds ratio for gastroenteritis associated with rainwater consumption compared with mains consumption was 0.84 (95% confidence interval 0.63-1.13). CONCLUSIONS: Gastroenteritis was found to be a significant cause of morbidity among young children. Young children, who were regular consumers of tank rainwater, were at no greater odds of gastroenteritis than those who drank treated public mains water.

A two-year prospective study of the health-related quality of life of children with chronic illness--the parents' perspective.

The aim of this study was to assess prospectively changes in the health-related quality of life (HRQL) of children and adolescents with diabetes, asthma or cystic fibrosis (CF). One hundred and twenty-two parents of children aged 10-16 years with asthma, diabetes, or CF were recruited from specialist paediatric clinics. Parents described their children's HRQL using the Child Health Questionnaire (PF98) at baseline, 6, 12, 18 and 24 months post-baseline. They reported that the general health of children with CF was significantly worse than that of children with asthma and diabetes at baseline. In other domains there were few differences between the HRQL of children in the three groups. In several domains, the HRQL of children with asthma or diabetes improved over the 2 years of the study. This improvement was less evident for children with CF.

A South Australian population-based study of congenital talipes equinovarus.

The aims of this study were to provide a population-based prevalence for congenital talipes equinovarus (CTEV), to conduct an epidemiological investigation into the risk factors for CTEV and describe associated features. The study used a retrospective case-control design of CTEV notified to the South Australian Birth Defects Register between 1986 and 1996 inclusive, linking characteristics of mother and baby from the perinatal data collection. The prevalence of isolated CTEV was 1.1/1000 total births (n = 231). Four factors were significantly associated with an increased risk of CTEV: maternal Aboriginal race (ORadj = 2.0; 95% CI 1.1, 3.6), male gender (ORadj = 2.4; 95% CI 1.8, 3.2), maternal anaemia (ORadj = 1.8; 95% CI 1.0, 2.9) and maternal hyperemesis (ORadj = 3.6; 95% CI 1.3, 9.8). The prevalence of CTEV associated with another birth defect or syndrome (n = 157) was 0.7/1000 total births. CTEV was associated with specific birth defects and also with oligohydramnios when another birth defect was present.

The relationship between health-related quality of life, pain and coping strategies in juvenile idiopathic arthritis.

OBJECTIVES: To investigate the relationship between health-related quality of life (HRQL), experience of pain and pain coping strategies in children with juvenile idiopathic arthritis (JIA). To compare reports describing these variables obtained from children and their parents. METHODS: Participants were 59 children aged 8 to 18 yr with JIA and their parents. Parents and children completed the PedsQL generic core scales and arthritis module, the visual analogue scale of the Varni-Thompson Pediatric Pain Questionnaire, and the Waldron/Varni Pediatric Pain Coping Inventory. Parents rated children's functional disability using the Childhood Health Assessment Questionnaire. RESULTS: Parents reported significantly lower scores (indicating worse HRQL) than children on five of the eight PedsQL scales rating children's HRQL. Parents and children reported a significant negative relationship between pain levels and the PedsQL scores assessing children's physical, emotional and social functioning. They also reported a significant negative relationship between scores on several pain coping scales and scores on the PedsQL scales. However, the pattern of these relationships varied for reports from parents and children. CONCLUSIONS: Pain intensity and pain coping strategies have a significant and independent relationship with several domains that comprise the HRQL of children with JIA. However, parents and children have differing perceptions of the nature of these relationships. The differences emphasize the importance of clinicians obtaining information about children's HRQL, pain levels and pain coping strategies from both parents and children.

Prevalence of gastroenteritis among 4-year-old children in South Australia.

The aim of this study was to determine the prevalence of gastroenteritis among children aged 4 years in South Australia. A cross-sectional survey of 9543 South Australian children aged 4 years was undertaken. Parents completed a questionnaire on behalf of their child who had attended a pre-school health check in 1998. The questionnaire covered gastrointestinal and respiratory symptoms experienced by the child in the previous 2 weeks and other risk factors for gastroenteritis. The 2-week prevalence of gastroenteritis among 4-year-old children was 14.2%. The major risk factors for gastroenteritis were presence of persons who had gastroenteritis inside the home, contact with persons who had gastroenteritis outside the home, antibiotic use and sore throat. Medical attention was sought for 20% of children who had gastroenteritis. Gastroenteritis is a significant cause of morbidity among young children and presents a considerable burden on the community. A substantial proportion of these occurrences of highly credible gastrointestinal symptoms may be manifestations of respiratory infections.

Health-service use by children with asthma over a 6-month period.

OBJECTIVES: The present study aims to describe the use of health services by children with asthma, and examine disease-specific, parental and sociodemographic variables associated with different levels of health-service utilization. METHODS: Parents of 135 children attending an emergency room (ER) completed questionnaires measuring the children's asthma symptoms, and sociodemographic and psychological variables. Parents were contacted monthly for 6 months to document the number of planned and unplanned visits to hospital and community health-care services for asthma. RESULTS: At least one further unplanned visit to the ER was made by 37% of children, while 62% made at least one unplanned visit to a general practitioner (GP). Fifty-five per cent made planned review visits to a GP, 30% to paediatricians and 5% to hospital clinics. After controlling for the level of asthma symptoms, parental anxiety and parental perceptions of children's vulnerability were associated with unplanned GP visits (P = 0.05 and P = 0.01, respectively); a planned review visit and the child being admitted to hospital for the index attack were associated with unplanned ER visits (P = 0.05 and P = 0.004, respectively). CONCLUSIONS: Children with asthma more frequently attend GP services than hospital services for both planned and unplanned asthma management. Different variables predict the unplanned use of GP and ER services. Understanding these differences is imperative if children and families are to make the most effective use of health services.

Pulmonary volume recruitment manoeuvre restores pulmonary compliance and resistance after apnoea in anaesthetized lambs.

BACKGROUND: We studied the effects of an episode of induced apnoea on the dynamic compliance (Crs) and resistance (Rrs) of the respiratory system in anaesthetized lambs and investigated the mechanisms underlying the effectiveness of a timed reexpansion inspiratory manoeuvre (TRIM). METHODS: Following 2 min of apnoea, three manoeuvres were randomly performed: (i) control: reventilated without TRIM using initial settings and gas composition of 30% oxygen in 70% nitrous oxide; (b) T1: TRIM with 30% oxygen in 70% nitrous oxide, followed by reventilation with the initial settings; and (c) T2: preoxygenate with 100% oxygen, apnoea, then TRIM with 100% oxygen, then reventilation with 100% oxygen at the initial settings. The percentage change in Crs and Rrs was calculated at first breath, second breath, 10, 20, 40, 60, 90, 120 and 180 s postapnoea. RESULTS: Mean control decreased 15% and did not return to baseline during the study period. TRIM increased mean Crs in T1 and T2 by 8% and 9%, respectively, at first breath and returned to baseline and did not deteriorate for the remainder of the study period. Mean Rrs in the control group increased 20% and did not return to baseline during the study period. Mean Rrs in T1 and T2 initially increased 17% and 27%, respectively, at first breath and returned to baseline within 40 s. CONCLUSIONS: These results demonstrate that significant deterioration occurs in Crs and Rrs following 2 min of apnoea in anaesthetized lambs, which is not corrected with normal ventilation but is rapidly and completely reversed with a TRIM. This supports our hypothesis that volume recruitment of alveoli is an effective manoeuvre in restoring lung function. The practice of preoxygenation is also reinforced as the lambs maintained maximal oxygen saturation if they were ventilated with 100% oxygen prior to the 2 min of apnoea.

Depression among Australian adolescents.

OBJECTIVES: To examine the prevalence and factors associated with depression in Australian adolescents. DESIGN: A representative, multistage probability sample of Australian households conducted in 1998 (part of the National Survey of Mental Health and Well-being). Adolescents completed self-report questionnaires and parents were interviewed using a lay-administered, structured psychiatric interview and several questionnaires. PARTICIPANTS: 1,490 adolescents aged 13-17 years and their parent or main caregiver. MAIN OUTCOME MEASURES: Prevalence of depression in adolescents, as reported by parents and by adolescents themselves; demographic factors; health-risk behaviours; and rate of use of support services. RESULTS: Of the 1,490 adolescents originally sampled, 150 (10%) did not complete responses to questions on depression and were excluded from the analysis. Seventy of the remaining 1340 adolescents (5.2%; 95% CI, 4.0%-6.4%) met criteria for self-reported depression. Agreement between parent- and adolescent-reported depression was poor (kappa=0.27). Adolescent-reported depression was associated with increased suicide plans (odds ratio [OR], 2.83; 95% CI, 1.19-6.70) and attempts (OR, 9.05; 95% CI, 3.49-23.50) in the previous year, use of marijuana 10 or more times in the previous month (OR, 2.88; 95% CI, 1.25-6.64), having conduct disorder (OR, 4.09; 95% CI, 1.23-13.63) and use of school support services (OR, 4.71; 95% CI, 1.82-12.22). Those who used any kind of support service (24/70; 34%) used a mean of 2.9 services (mode, 2; range, 1-5). Three per cent (2/70) of depressed adolescents had been treated with antidepressants. CONCLUSIONS: Depressed adolescents exhibit higher rates of health-risk behaviours and psychosocial impairment than non-depressed adolescents, but only a small number receive appropriate treatment. Staff working in school-based services should be trained to identify adolescents with depression and facilitate referral for treatment.

Reduced total plasma homocyst(e)ine in children and adolescents with type 1 diabetes.

OBJECTIVES: The objective was to investigate total plasma homocyst(e)ine (tHcy), methylenetetrahydrofolate reductase (MTHFR) genotype, and the contribution of diet to homocysteine values in children and adolescents with type 1 diabetes and a control group. STUDY DESIGN: A total of 78 children with type 1 diabetes and 59 members of an age- and sex-matched control group were recruited. Fasting samples were collected for tHcy, MTHFR genotype, serum vitamin B(12), serum folate, red cell folate, and plasma creatinine. Food frequency questionnaires targeted intake of folate, vitamin B(6), and vitamin B(12). RESULTS: Fasting tHcy was reduced in patients compared with the control group (4.7 vs 5.9 micromol/L, P <.001). Serum folate (P =.002), red cell folate(P <.001), and serum vitamin B(12) (P =.005) were higher, and plasma creatinine was lower. A significant difference in tHcy values between patients and the control group persisted after correction was done for these factors (r = 0.1, P =.02). No difference was seen in the frequency of MTHFR polymorphisms. tHcy was not elevated in those patients with the 677TT or 677T/1298C genotypes, although red cell folate was significantly higher in members of the case (P =.01) and control groups (P =.05) with a 677 TT genotype. Dietary intake of folate correlated with serum folate (r = 0.4,P =.005). CONCLUSION: tHcy values are lower in children and adolescents with type 1 diabetes. Higher serum levels of folic acid and vitamin B(12), reflecting differences in dietary intake between children with diabetes and members of a control group, partially account for this difference.

Efficacy of once-daily tobramycin monotherapy for acute pulmonary exacerbations of cystic fibrosis: a preliminary study.

Our objective was to compare the efficacy, safety, and microbiology of once-daily intravenous (IV) tobramycin with conventional 8-hourly tobramycin/ceftazidime IV therapy for acute Pseudomonas aeruginosa (PA) pulmonary exacerbations in cystic fibrosis (CF). CF patients with PA-induced pulmonary exacerbations were allocated to receive either once-daily tobramycin (Mono) or conventional therapy with tobramycin/ceftazidime given 8-hourly (Conv). The two longitudinal groups received therapy in a double-blind, randomized manner over a period of 2 years. Tobramycin doses were adjusted to achieve a daily area under the time-concentration curve of 100 mg x hr/L in both groups. Results were assessed for both short-term changes (efficacy and safety after 10 days of IV antibiotics during acute exacerbations) and long-term changes (efficacy, safety, and sputum microbiology between study entry and exit). Pulmonary function tests (PFTs) on admission were similar in both groups. After 10 days of IV antibiotics, absolute mean improvements in percent of predicted PFTs were 12.8, 12.1, and 13.7 for forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), and forced expired flow between 25--75% of FVC (FEF(25--75%)) in the Conv group (n = 51 admissions) compared to 10.6, 9.9, and 10.6 in the Mono group (n = 47)(P<0.05 for all). Sixteen percent in the Conv group and 15% of patients in the Mono group did not respond to therapy by day 10. Long-term PFT patterns were similar for the Conv and Mono groups. The time between admissions did not differ. The Mono group showed a significant increase in tobramycin minimum inhibitory concentrations (MICs) against PA from study entry to study exit (P = 0.02, n = 27 strains); this failed to reach significance in the Conv group (P = 0.08, n = 25). There was no significant increase in the number of isolates, with MIC> or =8 mg/L in both groups. No short- or long-term changes in audiology or serum creatinine were found in either group. After 10 days of IV therapy, the urinary enzyme N-acetyl-beta-d-glucosaminidase/creatinine ratios increased in both groups (P0.05). This increase was greater in the Conv compared to the Mono group (P < 0.05). We conclude that this pilot study indicates once-daily tobramycin therapy to be as effective and safe as conventional 8-hourly tobramycin/ceftazidime therapy. Combination antibacterial therapy appears to offer no clinical advantage over once-daily tobramycin monotherapy. Tobramycin once-daily monotherapy is a potential alternative to conventional IV antibacterial therapy which deserves further investigation, including the impact on susceptibility of PA to tobramycin.