Effects of low-dose estrogen replacement during childhood on pubertal development and gonadotropin concentrations in patients with Turner syndrome: results of a randomized, double-blind, placebo-controlled clinical trial.

CONTEXT: The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined. OBJECTIVE: The aim of the study was to assess the effects of an individualized regimen of low-dose ethinyl estradiol (EE2) during childhood from as early as age 5, followed by a pubertal induction regimen starting after age 12 and escalating to full replacement over 4 years. DESIGN: This study was a prospective, randomized, double-blind, placebo-controlled clinical trial. SETTING: The study was conducted at two US pediatric endocrine centers. SUBJECTS: Girls with Turner syndrome (n = 149), aged 5.0-12.5 years, were enrolled; data from 123 girls were analyzable for pubertal onset. INTERVENTION(S): Interventions comprised placebo or recombinant GH injections three times a week, with daily oral placebo or oral EE2 during childhood (25 ng/kg/d, ages 5-8 y; 50 ng/kg/d, ages >8-12 y); after age 12, all patients received escalating EE2 starting at a nominal dosage of 100 ng/kg/d. Placebo/EE2 dosages were reduced by 50% for breast development before age 12 years, vaginal bleeding before age 14 years, or undue advance in bone age. MAIN OUTCOME MEASURES: The main outcome measures for this report were median ages at Tanner breast stage ≥2, median age at menarche, and tempo of puberty (Tanner 2 to menarche). Patterns of gonadotropin secretion and impact of childhood EE2 on gonadotropins also were assessed. RESULTS: Compared with recipients of oral placebo (n = 62), girls who received childhood low-dose EE2 (n = 61) had significantly earlier thelarche (median, 11.6 vs 12.6 y, P < 0.001) and slower tempo of puberty (median, 3.3 vs 2.2 y, P = 0.003); both groups had delayed menarche (median, 15.0 y). Among childhood placebo recipients, girls who had spontaneous breast development before estrogen exposure had significantly lower median FSH values than girls who did not. CONCLUSIONS: In addition to previously reported effects on cognitive measures and GH-mediated height gain, childhood estrogen replacement significantly normalized the onset and tempo of puberty. Childhood low-dose estrogen replacement should be considered for girls with Turner syndrome.

Epidemic of invasive pneumococcal disease, western Canada, 2005-2009.

In Canada before 2005, large outbreaks of pneumococcal disease, including invasive pneumococcal disease caused by serotype 5, were rare. Since then, an epidemic of serotype 5 invasive pneumococcal disease was reported: 52 cases during 2005, 393 during 2006, 457 during 2007, 104 during 2008, and 42 during in 2009. Of these 1,048 cases, 1,043 (99.5%) occurred in the western provinces of Canada. Median patient age was 41 years, and most (659 [59.3%]) patients were male. Most frequently representing serotype 5 cases (compared with a subset of persons with non-serotype 5 cases) were persons who were of First Nations heritage or homeless. Restriction fragment-length polymorphism typing indicated that the epidemic was caused by a single clone, which multilocus sequence typing identified as sequence type 289. Large pneumococcal epidemics might go unrecognized without surveillance programs to document fluctuations in serotype prevalence.

Evaluation of a multi staged professional development course for practising pharmacists in anticoagulation management.

BACKGROUND: With the evolution of pharmacist prescriptive authority in Alberta, Canada, professional development courses need to impact change in daily practice. We designed a multi stage course targeting anticoagulation management with several components: (1) a print-based course to develop foundational knowledge; (2) a 2-day workshop; (3) a 3-day experiential programme; (4) distance mentorship to practice site; and (5) two full-day mentorship meetings. OBJECTIVE: To assess the impact of a comprehensive anticoagulation professional development course on practising pharmacists' knowledge, confidence and daily practice, with documentation of resources for the mentorship phases. METHODS: A mixed method of evaluation using surveys to assess pharmacist knowledge and confidence and semi-structured interviews to assess the impact on practice. Surveys were conducted prior to and following the workshop, after the experiential training and 4-6 months following completion of the workshop. Interviews were conducted following the experiential training and 4-6 months after the workshop. RESULTS: Enrolment for the complete multi stage course was limited to 12 pharmacists, while another 59 completed the course to the end of the workshop. Pharmacists completing the entire course had improved knowledge scores following the workshop, and between the workshop and 3-day experiential. These scores declined at 4-6 months. Improvements in confidence occurred throughout the course. At the final interview, all pharmacists indicated a positive impact on their practice. Mentorship was feasible and imperative to offer security to facilitate practice change. CONCLUSIONS: Overall, this comprehensive multi stage course improved knowledge, confidence and practice for pharmacists.

Sustained impact of anticoagulant control achieved in an anticoagulation management service after transfer of management to the primary care physician.

STUDY OBJECTIVES: To determine whether the impact of anticoagulant control achieved in an Anticoagulation Management Service (AMS) is sustained after transfer of anticoagulation management to the primary care physician (PCP), and to assess patient satisfaction with their anticoagulation management by both the AMS and PCP. DESIGN: Prospective, randomized trial. SETTING: Pharmacist-directed ambulatory AMS located in a tertiary medical care facility and PCP practices in Canada. PATIENTS: Sixty-two adults who had received at least 6 months of warfarin therapy managed by the AMS. INTERVENTION: Patients were randomly assigned to remain with AMS care (32 patients) or to transfer their anticoagulation management care to their PCP (30 patients). After 4.5 months of care, patients in both groups completed a validated survey instrument assessing their satisfaction with the management of their warfarin therapy. MEASUREMENTS AND MAIN RESULTS: Of 295 patients screened, most were excluded from the study for denying consent or for having previous bleeding or clotting complications while taking warfarin. Patients in the AMS and PCP groups who completed the study were similar in age (median 70 and 76 yrs, respectively), and most had atrial fibrillation as an indication for warfarin (75% and 83%, respectively). The primary outcome measure-mean percentage of time within the desired international normalized ratio (INR) range after 6 months-was compared between the two groups, using both the actual range (INR 2.5 ± 0.5) and an expanded range (INR 2.5 ± 0.7). No significant difference was noted in this outcome between the groups (73.5 ± 19.1% vs 76.9 ± 24.5% for the AMS vs PCP groups, p=0.54). Other outcome measures were rates of thrombotic and hemorrhagic events resulting in emergency department visits or hospitalizations, patients' overall satisfaction with warfarin therapy, and patients' preferred anticoagulation management strategy. Two hemorrhagic events and one thrombotic event occurred in each group. Patients were more satisfied with their anticoagulant management by the AMS relative to PCP care (p=0.01), and given the choice, patients preferred AMS care (p=0.001). CONCLUSION: During this 6-month trial, anticoagulation control did not significantly differ between patients who continued to receive anticoagulation management by the AMS and those who transferred to their PCP for anticoagulation management, indicating that the effects of AMS care were sustained. Although patients were more satisfied and preferred to stay with AMS care, this study shows that select patients could have their anticoagulation care transferred to their PCP without compromising anticoagulation control.

Factors predicting mortality in invasive pneumococcal disease in adults in Alberta.

To define the factors associated with 30-day mortality among adult patients with invasive pneumococcal disease (IPD), we conducted a retrospective review of all cases of IPD in Alberta from 2000 to 2004. We hypothesized that multiple factors would be predictive of such mortality. We also examined the factors predictive of early (within 5 days of admission) mortality. We identified 1154 patients who met our inclusion criteria, 163 (14.1%) of whom died within 30 days. Over half (62.6%) of the deaths occurred within 5 days of admission. Ten factors were independently associated with increased 30-day mortality: 3 comorbidity factors-cancer within 5 years of diagnosis of IPD, diabetes, and cirrhosis; 4 complications-requirement for supplemental oxygen, mechanical ventilation, alteration of mental status, and cardiac arrest; 2 microorganism-related factors-infection with high- or infection with intermediate-mortality serotypes; and 1 treatment-related factor-treatment with a single antibiotic. Age 18-40 years and treatment with 2 antibiotics concurrently were associated with lower 30-day mortality. Comorbid illnesses were not contributory to early mortality (within 5 days of admission); instead, complications (alteration of mental status, requirement for supplemental oxygen, mechanical ventilation, and cardiac arrest) as well as infection with high-mortality serotypes and treatment with a single antibiotic were important. Age 18-40 years, infection with serotypes in the polysaccharide vaccine, and treatment with 2 or more than 2 antibiotics were associated with decreased early mortality. Early mortality accounted for 62.6% of the deaths. In conclusion, we found that mortality in IPD is multifactorial, the factors differ for 5- and 30-day mortality, and mortality is associated with host (age and complications), microorganism (pneumococcal serotypes), and therapeutic factors. Our data indicate that treatment with 2 or more antibiotics effective against Streptococcus pneumoniae should be used to treat IPD.

Streptococcus pneumoniae meningitis in Alberta pre- and postintroduction of the 7-valent pneumococcal conjugate vaccine.

OBJECTIVE: To describe the epidemiology, clinical characteristics, microbiology and outcomes of patients of all ages with Streptococcus pneumoniae meningitis two years pre- and postintroduction of a S pneumoniae 7-valent conjugate vaccine program in Alberta in children <2 years of age. METHODS: Between 2000 and 2004, all cases of invasive pneumococcal disease in Alberta were identified. From this cohort, patients with S pneumoniae meningitis were identified by chart review. Clinical data, laboratory data and in-hospital outcomes were collected. RESULTS: Of the 1768 cases of invasive pneumococcal disease identified between 2000 and 2004, 110 (6.2%) had S pneumoniae meningitis. The overall incidence was 0.7 per 100,000 persons and remained unchanged over the study period. The rate in children <2 years of age appeared to fall over time, from 10.5 per 100,000 persons in 2000 to five per 100,000 persons in 2004, although there was insufficient evidence of a statistically significant time trend within any age group. Overall, the mean age was 30 years and 47% were male. In-hospital mortality was 20%, ranging from 6% in those ≤2 years of age to 31% for those ≥18 years of age, despite appropriate antimicrobial therapy. CONCLUSION: The high mortality rate associated with S pneumoniae meningitis suggests that prevention by vaccination is critical. In children <2 years of age, there was a downward trend in the rate of S pneumoniae meningitis after implementation of the S pneumoniae 7-valent conjugate vaccine program, but rates were still high.

Radial forearm versus anterolateral thigh free flaps for laryngopharyngectomy defects: prospective, randomized trial.

OBJECTIVE: To investigate the use of anterolateral thigh flaps versus radial forearm free flaps for the reconstruction of laryngopharyngectomy defects in a prospective, randomized study. METHODS: Nineteen patients who were to undergo laryngopharyngectomy were randomized into either anterolateral thigh or radial forearm groups. The primary outcome measure was complication rate (eg, flap failure, fistula formation, pharyngeal stenosis). Secondary outcome measures included donor-site morbidity (limb function, cosmesis, pain). RESULTS: There was a significant (p = .04) increase in reconstructive complications in the anterolateral thigh group, including esophageal stenosis and pharyngeal fistulae. There was no significant difference in donor-site complications. CONCLUSION: There is an increased free flap complication rate without decreased flap donor-site morbidity when using the anterolateral thigh flap to reconstruct laryngopharyngectomy defects. As such, we recommend the radial forearm free flap as the preferred flap for reconstruction of laryngopharyngectomy defects.

Welders are at increased risk for invasive pneumococcal disease.

BACKGROUND: Welders are at increased risk of pulmonary infection and lobar pneumonia, likely due to significant occupational exposure to metal fumes. We hypothesized that welders would be at increased risk for invasive pneumococcal disease (IPD) compared to the general population. METHODS: A retrospective chart review of all patients with IPD in the province of Alberta, Canada (population approx. 3.3 million) was conducted from 2000 to 2004 to study the epidemiology of IPD. RESULTS: There were 18 cases identified in welders, giving an attack rate of 22.7 cases per 100,000 population per year (95% confidence interval (CI) 12.23-33.23). Compared with an attack rate of 8.7 cases per 100,000 population per year (95% CI 8.10-9.26) for the general adult population between ages 18 and 65 years, there was a 2.7-fold greater incidence of IPD in welders (95% CI 1.67-4.22, p<0.001). There was an increased prevalence of serotypes 4 and 8 compared to the general population. Eight of 18 cases were caused by serotypes in the 7-valent pneumococcal conjugate vaccine, 11 of 18 cases by serotypes in the 13-valent pneumococcal conjugate vaccine, and 18 of 18 cases by serotypes in the 23-valent pneumococcal polysaccharide vaccine. Seventeen patients had bacteremic pneumococcal pneumonia and one had meningitis; one person died due to infection. Fifteen of 18 patients were either current or former smokers, which was a higher rate than the general population adjusted for age and gender (odds ratio 2.976, 95% CI 0.908-9.729, p=0.084). CONCLUSIONS: Welders, particularly those who smoke, are at increased risk of IPD and should be considered for routine administration of the pneumococcal polysaccharide vaccine. Ongoing workplace measures to reduce exposure to metal fumes and promote smoking cessation should be reinforced.

Pneumococcal peritonitis: Still with us and likely to increase in importance.

BACKGROUND: Pneumococcal peritonitis is uncommon and poorly understood. METHODS: As part of a five-year study (2000 to 2004) of invasive pneumococcal disease (IPD) in Alberta, all cases of peritonitis due to Streptococcus pneumoniae were reviewed and compared with all other cases of IPD. RESULTS: Twenty-three of 1768 (1.3%) IPD patients were found to have peritonitis. Patients with peritonitis were more likely to have cirrhosis, hepatitis C, alcoholism and HIV/AIDS, than the remainder of the patients with IPD. The all-cause mortality did not differ between the two groups. Peritonitis was classified as primary in nine (39%) patients, secondary in 12 (52%) patients, and genitourinary in females, specifically, in two (9%) patients. Pneumococcal serotypes causing peritonitis were under-represented in current vaccines - 17% among peritonitis patients versus 53% for the remainder of IPD patients for the 7-valent pneumococcal conjugate vaccine, and 56% versus 86% for the 23-valent pneumococcal polysaccharide vaccine. CONCLUSIONS: Peritonitis represents a small subset of patients with IPD, but one that is likely to grow in importance given the increase in the number of patients with hepatitis C and HIV, and the reduced coverage of peritonitis serotypes in currently available vaccines.

Cardiac EASE (Ensuring Access and Speedy Evaluation) - the impact of a single-point-of-entry multidisciplinary outpatient cardiology consultation program on wait times in Canada.

BACKGROUND: Universal access to health care is valued in Canada but increasing wait times for services (eg, cardiology consultation) raise safety questions. Observations suggest that deficiencies in the process of care contribute to wait times. Consequently, an outpatient clinic was designed for Ensuring Access and Speedy Evaluation (Cardiac EASE) in a university group practice, providing cardiac consultative services for northern Alberta. Cardiac EASE has two components: a single-point-ofentry intake service (prospective testing using physician-approved algorithms and previsit triage) and a multidisciplinary clinic (staffed by cardiologists, nurse practitioners and doctoral-trained pharmacists). OBJECTIVES: It was hypothesized that Cardiac EASE would reduce the time to initial consultation and a definitive diagnosis, and also increase the referral capacity. METHODS: The primary and secondary outcomes were time from referral to initial consultation, and time to achieve a definitive diagnosis and management plan, respectively. A conventionally managed historical control group (three-month pre-EASE period in 2003) was compared with the EASE group (2004 to 2006). The conventional referral mechanism continued concurrently with EASE. RESULTS: A comparison between pre-EASE (n=311) and EASE (n=3096) revealed no difference in the mean (+/- SD) age (60+/-16 years), sex (55% and 52% men, respectively) or reason for referral, including chest pain (31% and 40%, respectively) and arrhythmia (27% and 29%, respectively). Cardiac EASE reduced the time to initial cardiac consultation (from 71+/-45 days to 33+/-19 days) and time to a definitive diagnosis (from 120+/-86 days to 51+/-58 days) (P<0.0001). The annual number of new referrals increased from 1512 in 2002 to 2574 in 2006 due to growth in the Cardiac EASE clinic. The number of patients seen through the conventional referral mechanism and their wait times remained constant during the study period. CONCLUSIONS: Cardiac EASE reduced wait times, increased capacity and shortened time to achieve a diagnosis. The EASE model could shorten wait times for consultative services in Canada.

Survival in cystic neoplasms of the pancreas.

BACKGROUND: The natural history of pancreatic cystic neoplasms remains poorly understood despite growing evidence on the subject. Pancreatic cysts display a wide spectrum of pathological phenotypes, each associated with a different prognostic implication. Many pancreatic cysts are of undetermined malignant potential at presentation and remain so until surgically resected. While the survival rates of patients with malignant cysts are known to be poor, survival rates in patients with undetermined pancreatic cysts are unknown. OBJECTIVE: To identify the factors associated with survival in a group of patients diagnosed with a pancreatic cyst(s). METHODS: The present study was a retrospective multicentre review of pancreatic cystic neoplasms. All patients with a diagnosis of a neoplastic pancreatic cyst from 1994 to 2003 were identified at five different institutions in Edmonton, Alberta. The data collected included patient age, sex, imaging modality, cyst location, cyst size, number of cysts, comorbid illnesses, history of upper abdominal surgery, previous cancer, previous or concurrent metastases, symptoms (pain, upper gastrointestinal bleeding, signs of biliary obstruction, nausea/vomiting), remarkable radiological features, elevated amylase or lipase, type of pancreatic surgery, final pathology (benign or malignant) and overall survival. Survival models were used to assess whether any covariates were predictors of the survival time. Patient data were plotted using the Kaplan-Meier method. The resulting plot was used to calculate survival in the cohort. RESULTS: In total, 64 patients were identified as having neoplastic pancreatic cysts from 1994 to 2003 at the five institutions. The median overall patient survival time was 86 months. The median age at diagnosis for the patient population was 73 years, with 40 patients being women. Univariate analysis revealed that the risk of death was associated with patient age, sex and history of major comorbid illness. Multivariate models identified increased patient age and male sex as the factors that correlated most strongly with decreased overall survival. CONCLUSION: Overall survival in patients with neoplastic pancreatic cysts is determined by patient factors (ie, age and sex) rather than factors descriptive of the cyst such as size and morphology. No conclusions could be made regarding the relationship between cyst pathology and patient survival.

Serotypes and antimicrobial susceptibilities of invasive Streptococcus pneumoniae pre- and post-seven valent pneumococcal conjugate vaccine introduction in Alberta, Canada, 2000-2006.

Alberta, Canada introduced the Streptococcus pneumoniae seven valent conjugate vaccine (PCV7) program for children less than 2 years of age in September 2002. We determined the rates of invasive pneumococcal disease in Alberta, Canada 2 years pre- and 4 years post-PCV7 introduction (2000-2006) as well as the rates of antibiotic resistance and serotype distribution in this same time period. Overall, PCV7 serotypes decreased 61% from 2000 to 2006. The greatest decrease in incidence of invasive pneumococcal disease occurred in children less than 2 years of age declining from a high of 96.7/100,000 (2000) to 25.8/100,000 (2006) (P<0.0001). Non-susceptibility of S. pneumoniae isolates to penicillin dropped significantly from 14% in 2000 to 4.6% in 2006 (P<0.0001). Non-susceptible erythromycin isolates also decreased from 8.8% (2000) to 5.8% (2006) (P=0.13). The introduction of PCV7 in Alberta, Canada has decreased the incidence of invasive pneumococcal disease in Alberta as well as resulting in a decrease in antibiotic resistance over this same time frame, principally for penicillin resistance.