This study presents constrained maximum likelihood derivations of the design parameters of noninferiority trials for binary outcomes with the margin defined on the odds ratio (ψ) or risk-difference (δ) scale. The derivations show that, for trials in which the group-specific response rates are equal under the point-alternative hypothesis, the common response rate, π(N), is a fixed design parameter whose value lies between the control and experimental rates hypothesized at the point-null, {π(C), π(E)}. We show that setting π(N) equal to the value of π(C) that holds under H(0) underestimates the overall sample size requirement. Given {π(C), ψ} or {π(C), δ} and the type I and II error rates, or algorithm finds clinically meaningful design values of π(N), and the corresponding minimum asymptotic sample size, N=n(E)+n(C), and optimal allocation ratio, γ=n(E)/n(C). We find that optimal allocations are increasingly imbalanced as ψ increases, with γ(ψ)<1 and γ(δ)≈1/γ(ψ), and that ranges of allocation ratios map to the minimum sample size. The latter characteristic allows trialists to consider trade-offs between optimal allocation at a smaller N and a preferred allocation at a larger N. For designs with relatively large margins (e.g. ψ>2.5), trial results that are presented on both scales will differ in power, with more power lost if the study is designed on the risk-difference scale and reported on the odds ratio scale than vice versa.

Objective

To examine the risk of treatment emergent, cardiovascular serious adverse events associated with varenicline use for tobacco cessation.

Design

Meta-analysis comparing study effects using four summary estimates.

Data sources

Medline, Cochrane Library, online clinical trials registries, and reference lists of identified articles.

Review methods

We included randomised controlled trials of current tobacco users of adult age comparing use of varenicline with an inactive control and reporting adverse events. We defined treatment emergent, cardiovascular serious adverse events as occurring during drug treatment or within 30 days of discontinuation, and included any ischaemic or arrhythmic adverse cardiovascular event (myocardial infarction, unstable angina, coronary revascularisation, coronary artery disease, arrhythmias, transient ischaemic attacks, stroke, sudden death or cardiovascular related death, or congestive heart failure).

Results

We identified 22 trials; all were double blinded and placebo controlled; two included participants with active cardiovascular disease and 11 enrolled participants with a history of cardiovascular disease. Rates of treatment emergent, cardiovascular serious adverse events were 0.63% (34/5431) in the varenicline groups and 0.47% (18/3801) in the placebo groups. The summary estimate for the risk difference, 0.27% (95% confidence interval -0.10 to 0.63; P = 0.15), based on all 22 trials, was neither clinically nor statistically significant. For comparison, the relative risk (1.40, 0.82 to 2.39; P = 0.22), Mantel-Haenszel odds ratio (1.41, 0.82 to 2.42; P = 0.22), and Peto odds ratio (1.58, 0.90 to 2.76; P = 0.11), all based on 14 trials with at least one event, also indicated a non-significant difference between varenicline and placebo groups.

Conclusions

This meta--analysis--which included all trials published to date, focused on events occurring during drug exposure, and analysed findings using four summary estimates-found no significant increase in cardiovascular serious adverse events associated with varenicline use. For rare outcomes, summary estimates based on absolute effects are recommended and estimates based on the Peto odds ratio should be avoided.

Background

The authors previously developed and validated the Cancer of the Prostate Risk Assessment (CAPRA) score to predict prostate cancer recurrence based on pretreatment clinical data. They aimed to develop a similar postsurgical score with improved accuracy via incorporation of pathologic data.

Methods

A total of 3837 prostatectomy patients in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE™) national disease registry were analyzed. Cox regression was used to determine the predictive power of preoperative prostate-specific antigen (PSA), pathologic Gleason score (pGS), surgical margins (SM), extracapsular extension (ECE), seminal vesicle invasion (SVI), and lymph node invasion (LNI). Points were assigned based on the relative weights of these variables in predicting recurrence. The new postsurgical score (CAPRA-S) was tested and compared with a commonly cited nomogram with proportional hazards analysis, concordance (c) index, calibration plots, and decision-curve analysis.

Results

Recurrence appeared in 16.8% of the men; actuarial progression-free probability at 5 years was 78.0%. The CAPRA-S was determined by adding up to 3 points for PSA, up to 3 points for pGS, 1 point each for ECE and LNI, and 2 points each for SM and SVI. The hazard ratio for each point increase in CAPRA-S score was 1.54 (95% confidence interval, 1.49-1.59), indicating a 2.4-fold increase in risk for each 2-point increase in score. The CAPRA-S c-index was 0.77, substantially higher than 0.66 for the pretreatment CAPRA score and comparable to 0.76 for the nomogram. The CAPRA-S score performed better in both calibration and decision curve analyses.

Conclusions

The CAPRA-S offers good discriminatory accuracy, calibration, and ease of calculation for clinical and research settings.

Despite the importance of measuring weight and height at well-child visits, there are limited data on frequency of anthropometric documentation. The authors aimed to identify characteristics associated with missing weight and height documentation at preventive visits for children. Among preventive visits for children from birth to 18 years old, recorded in the National Ambulatory Medical Care and National Hospital Ambulatory Medical Care Surveys for 2005-2009, the authors found that 20.8% had missing weight and/or height (n = 19,033) documentation. Compared with infants younger than 2 years, school-age children (odds ratio [OR] = 1.30; 95% confidence interval [CI] = 1.03-1.64), and adolescents (OR = 1.61; 95% CI = 1.26-2.04) were more likely to lack documentation. Missing documentation was also more likely for visits with nonphysicians (OR = 4.53; 95% CI = 3.17-6.48) and nonpediatricians (OR = 2.63; 95% CI = 2.02-3.41) compared with pediatricians. Efforts to improve weight and height surveillance should be directed to clinics in which midlevel providers and nonpediatric physicians are caring for school-age children and adolescents.

Purpose

NCCN Guidelines® recommend annual prostate biopsies for men with low risk prostate cancer on active surveillance. We determined whether erectile function decreases with the number of biopsies experienced.

Materials and methods

During a median 3.2-year followup after prostate cancer diagnosis in 2003 to 2010 at our institution 427 men on active surveillance underwent a total of 1,197 biopsies and provided 1,398 erectile function evaluations via the Sexual Health Inventory for Men questionnaire. For analysis we decomposed the 25-point questionnaire responses into a 5-point erectile function score and a 3-level sexual activity status. We used separate models adjusted for patient characteristics to determine whether either outcome varied with biopsy exposure.

Results

At diagnosis the median age was 61 years and median prostate specific antigen was 5.3 ng/ml. Of the cases 70% were clinical stage cT1 and 93% were Gleason score less than 7. Of biopsies followed by evaluations 40% were the first undergone by the patient and 9% were the fifth to ninth. At the first erectile function evaluation 15% of men were inactive, 8% engage in stimulation and 77% engaged in intercourse. Sexual activity level changed in greater than 20% of respondents between evaluations. Adjusted erectile function scores were not associated with biopsy exposure cross-sectionally or longitudinally but they corresponded with the 50th, 63rd and 80th percentiles of erectile function by increasing sexual activity level. Similarly, sexual activity was not associated with biopsy exposure. Separated outcomes were more accurate and informative than Sexual Health Inventory for Men scores.

Conclusions

Our study had high power to detect erectile function-biopsy associations but it estimated that the effects were negligible. We recommend erectile function scores over Sexual Health Inventory for Men scores to avoid biased assessment of erectile function.

Objective

The aims of this study were to profile and compare the health and health services characteristics for children with special health care needs (CSHCN), with and without disabilities, and to determine factors associated with unmet need.

Methods

Secondary data analysis of the 2005-2006 National Survey of Children with Special Health Care Needs was conducted. The sociodemographics, health, and health services of CSHCN with and without disabilities were compared. Multivariable logistic regression was employed to examine factors associated with unmet need for health services.

Results

Children from minority racial and ethnic groups and children living in or near poverty were over-represented among CSHCN with disabilities, compared with other CSHCN. Statistically higher percentages of CSHCN with disabilities had behavioral problems (39.6% vs 25.2%), anxiety/depressed mood (46.1% vs 24.0%), and trouble making/keeping friends (38.1% vs 15.6%) compared with other CSHCN. Thirty-two percent of CSHCN with disabilities received care in a medical home compared with 51% of other CSHCN. CSHCN with disabilities had higher rates of need and unmet need than other CSHCN for specialty care, therapy services, mental health services, home health, assistive devices, medical supplies, and durable medical equipment. The adjusted odds of unmet need for CSHCN with disabilities were 71% higher than for other CSHCN.

Conclusion

CSHCN with disabilities had more severe health conditions and more health services need, but they less commonly received care within a medical home and had more unmet need. These health care inequities should be amenable to policy and health service delivery interventions to improve outcomes for CSHCN with disabilities.

The soft zone in dentine beneath the dentino-enamel junction is thought to play an important role in tooth function, strain distribution and fracture resistance during mastication. Recently reported asymmetry in mechanical properties with tooth side may point at a basic property of tooth function. The aim of our study was to test if this asymmetry was reflected in the nano- and micromechanical properties of dentine. We investigated the mechanical properties of dentine on the buccal and lingual side of nine extracted human teeth using nano- and microindentation. Properties were analysed on the natural log scale, using maximum likelihood to estimate the parameters. Two-sided 0.05-level likelihood ratio tests were used to assess the influences of surface (buccal versus lingual) and dentine depth, measured from the DEJ in crown dentine and from the CDJ in root dentine. Results showed the well known gradual increase in mechanical properties with increasing distance from the DEJ. Coronal dentine showed higher elastic modulus and hardness on the lingual side of teeth for all measurements, while root dentine was harder on the buccal side. Due to the subtlety of these effects and the small number of teeth studied, results failed to reach statistical significance. Results suggest that dentine nano- and micromechanical properties vary with tooth side in agreement with recent literature using macroscopic methods. They also reveal that buccal-lingual ratios of hardness are in opposite directions in crown and root dentine, suggesting compensatory functions.

Objective

To estimate the prevalence of and to identify factors associated with prolonged emergency department length-of-stay (ED-LOS) for admitted children.

Methods

Data were from the 2001-2006 National Hospital Ambulatory Medical Care Survey. The primary outcome was prolonged ED-LOS (defined as total ED time >8 hours) among admitted children. Predictor variables included patient-level (eg, demographics including race/ethnicity, triage score, diagnosis, and admission to inpatient bed vs intensive care unit), physician-level (intern/resident vs attending physician), and system-level (eg, region, metropolitan area, ED and hospital type, time and season, and diagnostic and therapeutic procedures) factors. Multivariable logistic regression was performed to identify independent predictors of prolonged ED-LOS.

Results

Median ED-LOS for admitted children was 3.7 hours. Thirteen percent of pediatric patients admitted from the ED experienced prolonged ED-LOS. Factors associated with prolonged ED-LOS for admitted children were Hispanic ethnicity (odds ratio [OR], 1.76; 95% confidence interval [95% CI], 1.10-2.81), ED arrival between midnight and 8 a.m. (OR, 2.80; 95% CI, 1.87-4.20), winter season (January-March: OR, 1.81; 95% CI, 1.20-2.74), computed tomography scan or magnetic resonance imaging (OR, 1.65; 95% CI, 1.05-2.58), and intravenous fluids or medications (OR, 1.81; 95% CI, 1.10-2.97). Children requiring ICU admissions (OR, 0.29; 95% CI, 0.11-0.77) or receiving pulse oximetry in the ED (OR, 0.52; 95% CI, 0.34-0.81) had a lower risk of experiencing prolonged ED-LOS.

Conclusions

We found that prolonged ED-LOS occurs frequently for admitted pediatric patients and is associated with Hispanic ethnicity, presentation during winter season, and early morning arrival. Potential strategies to reduce ED-LOS include improved availability of interpreter services and enhanced staffing and additional inpatient bed availability during winter season and overnight hours.

Objectives

A commercial restorative material, BondfillSB (BF), is a modification of 4-META/MMA-TBB resin cement. BF uses a self-etching primer and added pre-polymerized organic fillers. We compared BF with another self-etching system, EasyBond (EB), in shear bond strength, bonded interface characteristics to human dentin and contraction gap when used in bulk-filling.

Methods

Shear bond strength of BF and EB + Z100 (Z), bonded by different experience-level operators, was evaluated. Bonded interfaces were characterized by SEM, AFM, and AFM based nano-indentation. Contraction gaps (CG) at 0h and 24h after polymerization were evaluated for BF or EB bulk filled class I cavities. To meet the clinical recommendation, BF's powder was replaced by experimental radioopaque powder (BFO) for the CG study. EB was used with Z (EBZ) or with a resin marketed for bulk-fill base (SureFil-SDR-flow (EBSF)).

Results

Shear bond strengths (Mean ± Standard Deviation (S.D.)) of BF (37.4 ± 2.6 MPa; n=36) were higher and less variable than EBZ (18.2 ± 7.6 MPa; n=36) (p<0.0001, One-way ANOVA). Weibull characteristic strength (η) differed significantly between materials (p<0.0001) but not between operators (p=0.90). EBZ often had non-uniform interfaces and a wider band of reduced elastic modulus (E) of greater than 20 μm across the interface. BF had uniform interfaces and a smaller width of affected dentin under the interface (∼1 μm). There was a difference in dentin-E between EBZ and BF up to 9 μm from the interface (mixed-effects model; P=0.03). A stratified linear regression model used for CG. EBSF and BFO showed significantly smaller CG than EBZ at time 0. None of three combinations showed any significant change between 0h-CG and 24h-CG.

Significance

BF possessed bonding characteristics required to serve as a restorative.

Goals

To evaluate provider knowledge, attitudes and barriers to hepatitis B virus (HBV) care and management practices across diverse primary care settings.

Background

Factors influencing adherence to recommended HBV screening and management guidelines are poorly defined.

Materials and methods

Providers across various health care settings in San Francisco were surveyed. Multivariate analyses were used to identify factors associated with recommended HBV screening, vaccination, and disease monitoring.

Results

Of 277 (41.3%) responding providers, 42% reported performing HBV screening in >50% of at-risk patients, and 49%, HBV vaccination in >50% of eligible patients. Most reported appropriate monitoring of a majority of HBV-infected patients with alanine aminotransferase (79%) and HBV viral load (67%) every 6 to 12 months, but performed any hepatocellular carcinoma screening in 49%. Provider factors significantly associated with HBV screening were speaking an Asian language [odds ratio (OR), 3.27], offering HBV treatment (OR, 3.00), having >25% of Asian patients in practice (OR, 2.10), practicing in safety net settings (OR, 7.51) and having higher barrier score (OR, 0.74). Appropriate HBV monitoring was associated with provider speaking an Asian language (OR, 3.43) and provider age (OR, 0.68/decade). Hepatocellular carcinoma screening was associated with having >25% of patients speaking English as a second language (OR, 4.26) and practicing in safety net settings (OR, 0.14).

Conclusions

Rates of adherence to HBV guidelines were suboptimal irrespective of practice setting and were influenced by certain provider, patient and practice factors. This study reinforces the importance of engaging primary care providers in development, dissemination, and implementation of evidence-based HBV practice guidelines.