Population-based epidemiology of invasive pneumococcal infection in children in nine urban centers in Canada, 1994 through 1998

PURPOSE: To describe the epidemiology of invasive pneumococcal infections in Canadian children 0 to 12 years old. METHODS: At each of nine urban centers, active surveillance was conducted to identify all cases of invasive pneumococcal infection in children during 1994 to 1998. Postal codes were used to distinguish cases resident in defined urban areas from referral cases. Census data were obtained for each defined area to calculate age-specific incidence rates. Features of population-based cases were described. RESULTS: From an average defined population of approximately 1 million children, 937 eligible cases arose. Those 6 to 17 months old had the highest average incidence rate of 98.6/100 000/year. The average cumulative risk of infection was 1 in 460 between birth and 59 months, by which age 92% of cases had occurred. Among cases younger than 2 years of age, simple bacteremia accounted for 66%, pneumonia with bacteremia accounted for 14.7% and meningitis accounted for 11% (average incidence rate, 9.0/100 000/year). An underlying illness was present in 16% of all cases. The mortality rate was 1.8%. CONCLUSIONS: Invasive pneumococcal infections are relatively common in early childhood, based on 5 years of data from nearly 20% of the Canadian population ages 0 to 12 years. These data will be valuable for calculating the economic case for universal infant vaccination with newly available vaccines.     

Lipoproteins in the DCCT/EDIC cohort: associations with diabetic nephropathy

BACKGROUND: Lipoproteins may contribute to diabetic nephropathy. Nuclear magnetic resonance (NMR) can quantify subclasses and mean particle size of very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL), and LDL particle concentration. The relationship between detailed lipoprotein analyses and diabetic nephropathy is of interest. METHODS: In a cross-sectional study, lipoproteins from 428 women and 540 men from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort were characterized by conventional lipid enzymology, NMR, apolipoprotein levels, and LDL oxidizibility. Linear regression was performed for each lipoprotein parameter versus log albumin excretion rate (AER), with and without covariates for age, diabetes duration, HbA1c, hypertension, body mass index, waist-hip ratio, and DCCT treatment group. Significance was taken at P < 0.05. RESULTS: By multivariate analysis, conventional profile, total triglycerides, total- and LDL cholesterol, but not HDL cholesterol, were associated with AER. NMR-determined large, medium, and small VLDL were associated with AER in both genders (except large VLDL in women), and intermediate density lipoprotein (IDL) was associated with AER (men only). LDL particle concentration and ApoB were positively associated with AER (in men and in the total cohort), and there was a borderline inverse association between LDL diameter and AER in men. Small HDL was positively associated with AER and a borderline negative association was found for large HDL. No associations were found with ApoA1, Lp(a), or LDL oxidizibility. CONCLUSION: Potentially atherogenic lipoprotein profiles are associated with renal dysfunction in type 1 diabetes and further details are gained from NMR analysis. Longitudinal studies are needed to determine if dyslipoproteinemia can predict patients at risk of nephropathy, or if lipoprotein-related interventions retard nephropathy.     

Multicenter study assessing effects of heat and moisture exchanger use on respiratory symptoms and voice quality in laryngectomized individuals

OBJECTIVE: A multicenter study based in the United States assessed the heat-moisture exchanger effect on respiratory symptoms and "voice quality" of laryngectomees. PATIENTS AND MEASURES: The study group consisted of 81 consecutive laryngectomees (62 men and 19 women; mean age, 66 years; age range, 45 to 89 years), with a median follow-up of 3.5 years (range, 0.5 to 24 years). A structured questionnaire was used to assess 3-month results, and tally sheets recorded the frequency of cough-expectoration during first and last trial weeks. RESULTS: Compliance was 73% (n = 59); decrease in coughing, 68%; sputum production, 73%; forced expectoration, 60%; and need for stoma cleaning, 52% of these 59 patients. Regarding daily cough-expectoration frequency, a statistically significant decrease (P < 0.0001) was found between the first and last trial weeks. Regarding influence on voice quality, 46% of regular users reported improvement in intelligibility, 30% in loudness, 37% in fluency, and 40% in telephone intelligibility. Fourteen patients (19%) reported skin irritation, with discontinuation of 7 patients. CONCLUSION: The observed decrease in pulmonary symptoms and improvement in voice quality confirm earlier reports from the Netherlands, United Kingdom, and Spain indicating improvement in postlaryngectomy quality of life.     

Identifying vascular access complications among ESRD patients in Europe. A prospective,multicenter study

The pilot project of the Research Board of the EDTNA/ERCA was aimed at reviewing the management of vascular access (VA) in European dialysis centres (see August 1999 NN&I). In Part 1 of this study, centre policies related to VA management were investigated. In Part 2, detailed in this article, individual patients were prospectively followed for one year to identify VA-related complications. A cohort of 1,380 adult patients randomly selected from 47 centres in 16 European countries was followed for one year using a computerised data collection system. Data were collected at baseline after 6 and 12 months and each time a VA complication occurred. At the start of the observation period, 77% of patients had a native arteriovenous (AV) fistula, 10% had an AV graft, and 13% had a catheter for access. A total of 489 complications were noted during the one-year period. Most frequently observed were thrombosis, stenosis, infection, bleeding, and flow problems. Hospitalisation (mean duration = 6.2 days) was required in 39% of patients with complications, and 29% of complications resulted in a definitive loss of VA. Complications were more frequently observed in patients with catheters (27%) and AV grafts (37%) compared to those with an AV fistula (15%). The risk of thrombosis was more than four times higher and the risk of bleeding was more than six times higher if an AV graft was used compared to an AV fistula. Catheters presented an eightfold increased risk for patients of developing infections and access flow problems. [figure: see text] This study revealed the high complication rate in VA and strengthened the notion that the AV fistula is the superior access.     

A six-month randomized clinical trial comparing the intraocular pressure-lowering efficacy of bimatoprost and latanoprost in patients with ocular hypertension or glaucoma

PURPOSE: To compare the intraocular pressure (IOP)-lowering efficacy and safety of topical bimatoprost 0.03% with latanoprost 0.005%. DESIGN: Multicenter, randomized, investigator-masked clinical trial. METHODS: After washout of glaucoma medications, ocular hypertension or glaucoma patients were randomly assigned to once-daily bimatoprost 0.03% (n = 133) or latanoprost 0.005% (n = 136) for 6 months. The primary outcome measure was mean change from baseline IOP (8 AM, 12 PM, 4 PM). Secondary measures included mean IOP, ophthalmologic examination, adverse events, and the percentage of patients reaching specific target IOPs. RESULTS: Mean change from baseline IOP was significantly greater for bimatoprost patients than for latanoprost patients at all measurements on each study visit; 1.5 mm Hg greater at 8 AM (P <.001), 2.2 mm Hg greater at 12 PM (P <.001), and 1.2 mm Hg greater at 4 PM (P =.004) at month 6. At the end of the study, the percentage of patients achieving a > or = 20% IOP decrease was 69% to 82% with bimatoprost and 50% to 62% with latanoprost (P < or = .003). In addition, the distribution of patients achieving target pressures in each range (< or = 13 to < or = 15 mm Hg, >15 to < or = 18 mm Hg, and > 18 mm Hg) showed that bimatoprost produced lower target pressures compared with latanoprost at all times measured (P < or = .026). Few patients were discontinued for adverse events (6 on bimatoprost; 5 on latanoprost). On ophthalmologic examination, conjunctival hyperemia (P <.001) and eyelash growth (P =.064) were more common in bimatoprost patients. CONCLUSIONS: Bimatoprost is more effective than latanoprost in lowering IOP. Both drugs were well tolerated, with few discontinuations for adverse events.     

The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.     

Short-term correlations between clinical and MR imaging findings in relapsing-remitting multiple sclerosis

BACKGROUND AND PURPOSE: Despite extensive use of MR imaging to provide markers of multiple sclerosis (MS) activity and accumulated disease burden, the magnitude of the relationship between clinical and MR findings is still debated. Using data from the European/Canadian glatiramer acetate (GA) trial, we investigated short-term correlations between clinical and MR measures of disease activity in patients with relapsing-remitting MS (RRMS). METHODS: In a 9-month, double-blinded, placebo-controlled study, 239 patients with RRMS were randomly assigned to receive 20 mg GA (n = 119) or placebo (n = 120). Clinical assessment included monthly neurologic examinations with Expanded Disability Status Scale scoring and visits for symptoms suggestive of relapse. Dual-echo T2-weighted and pre- and postcontrast T1-weighted brain MR images were obtained at baseline and monthly during follow-up. Contrast-enhancing and new T2-hyperintense lesions were counted, and total T2-hyperintense and T1-hypointense lesion volumes were measured. RESULTS: Significant univariate correlations were found between the number of relapses during the study period and the number of enhancing lesions at baseline (r = 0.25) and during follow-up (r = 0.30) in the study population as a whole. Multivariable analysis showed that two independent factors were more strongly correlated with relapse frequency: the number of relapses during the 2 years before entry and the number of on-trial enhancing lesions, in the whole study population and in the placebo group. CONCLUSION: In RRMS, MR imaging measures of inflammatory activity are modestly but significantly correlated with the occurrence of clinical attacks over the short term. Clinical and MR imaging assessment can provide complementary outcome measures for RRMS trials.     

Predictive variables for malignant transformation in 452 patients with asymptomatic IgM monoclonal gammopathy

The natural history of asymptomatic IgM monoclonal gammopathies (MG) and variables predicting evolution to symptomatic lymphoproliferative disorders were investigated in 452 patients diagnosed from 1975 to 2001. Univariate and multivariate Cox models were used to identify possible predictors of disease progression. At a median follow-up of 49 months (range, 12 to 233), 41 cases (9.1%) evolved to symptomatic Waldenstrom's macroglobulinemia (n = 36), non-Hodgkin's lymphoma (n = 2), B-cell chronic lymphocytic leukemia (n = 1), IgM multiple myeloma (n = 1), and primary amyloidosis (n = 1); the median interval from diagnosis was 53 months (range, 12 to 154). The cumulative probabilities of transformation into a symptomatic lymphoproliferative disease at 5 and 10 years were 8% (95% confidence interval [CI], 6% to 12%) and 21% (95% CI, 16% to 29%), respectively. At univariate analysis, monoclonal component size and hemoglobin level as continuous parameters, lymphocytosis (>4 x 10(9)/L), bone marrow lymphoplasmacytoid infiltration (>10%), erythrocyte sedimentation rate (>40 mm/h), and detectable Bence Jones proteinuria were significantly related with evolution probability. At multivariate analysis, paraprotein level (P <.0001), hemoglobin level (P <.05), and lymphocytosis (P <.0001) independently predicted malignant evolution (P <.0001). In conclusion, patients with asymptomatic IgM-MG showing hematological features predictive of progression should be carefully monitored in view of an early treatment of the disease.