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1.  Persistent infection with human papillomavirus 16 or 18 is strongly linked with high-grade cervical disease 
We investigated the relationship between high-grade cervical disease (cervical intraepithelial neoplasia [CIN] 2, CIN3 or adenocarcinoma in situ) and persistent infection with HPV16 and/or HPV18 (HPV16/18) among 3970 women who received placebo in 3 clinical trials of a quadrivalent HPV vaccine. Statistical analysis (odds ratios, sensitivity, specificity, negative and positive predictive values, negative and positive likelihood ratios) showed that patients with a persistent infection with HPV16/18 had a much greater risk of HPV16/18-related high-grade cervical disease. Furthermore, subjects without a persistent infection with HPV16/18 were unlikely to have HPV16/18-related high-grade cervical disease. These results suggest that persistent infection with HPV16/18 meets the criteria for a surrogate endpoint for HPV16/18-related high-grade cervical disease and may be used as such in future clinical studies with prophylactic HPV vaccines and in natural history studies.
PMCID: PMC4964639  PMID: 26383553
cervical intraepithelial neoplasia; cervical cancer; statistics; HPV; Prentice criteria; surrogate endpoint
2.  Long-Term Follow-up Observation of the Safety, Immunogenicity, and Effectiveness of Gardasil™ in Adult Women 
PLoS ONE  2013;8(12):e83431.
Previous analyses from a randomized trial in women aged 24–45 have shown the quadrivalent HPV vaccine to be efficacious in the prevention of infection, cervical intraepithelial neoplasia (CIN) and external genital lesions (EGL) related to HPV 6/11/16/18 through 4 years. In this report we present long term follow-up data on the efficacy, safety and immunogenicity of the quadrivalent HPV vaccine in adult women.
Follow-up data are from a study being conducted in 5 sites in Colombia designed to evaluate the long-term immunogenicity, effectiveness, and safety of the qHPV vaccine in women who were vaccinated at 24 to 45 years of age (in the original vaccine group during the base study [n = 684]) or 29 to 50 years of age (in the original placebo group during the base study [n = 651]). This analysis summarizes data collected as of the year 6 post-vaccination visit relative to day 1 of the base study (median follow-up of 6.26 years) from both the original base study and the Colombian follow-up.
There were no cases of HPV 6/11/16/18-related CIN or EGL during the extended follow-up phase in the per-protocol population. Immunogenicity persists against vaccine-related HPV types, and no evidence of HPV type replacement has been observed. No new serious adverse experiences have been reported.
Vaccination with qHPV vaccine provides generally safe and effective protection from HPV 6-, 11-, 16-, and 18-related genital warts and cervical dysplasia through 6 years following administration to 24–45 year-old women.
Trial Registration NCT00090220
PMCID: PMC3877052  PMID: 24391768
3.  Reduction in medication errors in hospitals due to adoption of computerized provider order entry systems 
Medication errors in hospitals are common, expensive, and sometimes harmful to patients. This study's objective was to derive a nationally representative estimate of medication error reduction in hospitals attributable to electronic prescribing through computerized provider order entry (CPOE) systems.
Materials and methods
We conducted a systematic literature review and applied random-effects meta-analytic techniques to derive a summary estimate of the effect of CPOE on medication errors. This pooled estimate was combined with data from the 2006 American Society of Health-System Pharmacists Annual Survey, the 2007 American Hospital Association Annual Survey, and the latter's 2008 Electronic Health Record Adoption Database supplement to estimate the percentage and absolute reduction in medication errors attributable to CPOE.
Processing a prescription drug order through a CPOE system decreases the likelihood of error on that order by 48% (95% CI 41% to 55%). Given this effect size, and the degree of CPOE adoption and use in hospitals in 2008, we estimate a 12.5% reduction in medication errors, or ∼17.4 million medication errors averted in the USA in 1 year.
Our findings suggest that CPOE can substantially reduce the frequency of medication errors in inpatient acute-care settings; however, it is unclear whether this translates into reduced harm for patients.
Despite CPOE systems’ effectiveness at preventing medication errors, adoption and use in US hospitals remain modest. Current policies to increase CPOE adoption and use will likely prevent millions of additional medication errors each year. Further research is needed to better characterize links to patient harm.
PMCID: PMC3628057  PMID: 23425440
computerized provider order entry (CPOE); medication errors; medical order entry systems; medical informatics; adverse drug events
4.  Efficacy of Quadrivalent HPV Vaccine against HPV Infection and Disease in Males 
The New England journal of medicine  2011;364(5):401-411.
Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men.
We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status.
In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001).
Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age. (Funded by Merck and others; number, NCT00090285.)
PMCID: PMC3495065  PMID: 21288094
5.  Safety and Immunogenicity of a Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) Vaccine in HIV-Infected Children 7 to 12 Years Old 
Quadrivalent human papillomavirus vaccine (QHPV) is >95% effective in preventing infection with vaccine-type human papillomavirus. The safety and immunogenicity of QHPV are unknown in HIV-infected children.
HIV-infected children (N = 126)—age >7 to <12 years, with a CD4% ≥15—and on stable antiretroviral therapy if CD4% was <25—were blindly assigned to receive a dose of QHPV or placebo (3:1 ratio) at 0, 8, and 24 weeks. Adverse events were evaluated after each dose. Serum antibody against QHPV antigens was measured by a competitive Luminex immunoassay 1 month after the third QHPV dose.
The safety profile of QHPV was similar in the 2 study arms and to that previously reported for QHPV recipients. QHPV did not alter the CD4% or plasma HIV RNA. Seroconversion to all 4 antigens occurred in >96% of QHPV recipients and in no placebo recipients. Geometric mean titer was >27 to 262 times greater than the seropositivity cutoff value, depending on the antigen, but was 30%–50% lower against types 6 and 18 than those of age-similar historical controls.
QHPV was safe and immunogenic in this cohort of HIV-infected children. Efficacy trials are warranted.
PMCID: PMC3033215  PMID: 20574412
HPV vaccine; HIV infection; HPV antibody response
6.  Excess Mortality Following Hip Fracture: The Role of Underlying Health Status 
The long-term excess mortality associated with hip fracture remains controversial.
To assess the association between hip fracture and mortality, we used prospectively collected data on pre-fracture health and function from a representative sample of U.S. elders in the Medicare Current Beneficiary Survey (MCBS) to perform survival analyses with time-varying covariates.
Among 25,178 MCBS participants followed for a median duration of 3.8 years, 730 sustained a hip fracture during follow-up. Both early (within 6 months) and subsequent mortality showed significant elevations in models adjusted only for age, sex and race. With additional adjustment for pre-fracture health status, functional impairments, comorbid conditions and socioeconomic status, however, increased mortality was limited to the first six months after fracture (hazard ratio [HR]: 6.28, 95% CI: 4.82, 8.19). No increased mortality was evident during subsequent follow-up (HR: 1.04, 95% CI: 0.88, 1.23). Hip-fracture-attributable population mortality ranged from 0.5% at age 65 among men to 6% at age 85 among women.
Hip fracture was associated with substantially increased mortality, but much of the short-term risk and all of the long-term risk was explained by the greater frailty of those experiencing hip fracture.
PMCID: PMC2729704  PMID: 17726622
attributable risk; hip fracture; mortality; osteoporosis
7.  Comorbidity Risk-Adjustment Strategies are Comparable Among Persons with Hip Fracture 
Journal of clinical epidemiology  2008;61(6):580-587.
To determine the magnitude and importance of declines in model performance associated with altering the source data and time frame from which comorbid conditions were identified in claims-based risk-adjustment among persons with hip fracture.
Study Design and Setting
Medicare claims data were used to identify incident hip fracture cases in 1999. Three risk-adjustment instruments were evaluated: one by Iezzoni, the Charlson Index (Romano adaptation), and the Clinical Classification Software (CCS). Several implementation strategies, defined by altering data source (MedPar and/or Part B claims) and time frame (index hospitalization and/or 1-year pre-period), were assessed for each instrument. Logistic regression was used to predict one-year mortality and model performance was compared.
Each instrument had modest ability to predict 1-yr mortality following hip fracture. The CCS performed best overall (c = 0.76), followed by the Iezzoni (c = 0.73) and Charlson models (c = 0.72). Although each instrument performed most favorably when applied to both inpatient and outpatient claims and when comorbidities were considered during the pre-period, varying data source and time frame had trivial effects on model performance.
The similar predictive ability of the three risk adjustment instruments suggests that ease of implementation be a key consideration in choosing an approach for hip fracture populations.
PMCID: PMC2653048  PMID: 18471662
risk adjustment; hip fracture; Medicare; administrative data; prospective cohort; ROC analysis

Results 1-7 (7)