Key measurement concepts and appropriate clinical outcome assessments in pediatric achondroplasia clinical trials.

BACKGROUND: This study aimed to identify fit-for-purpose clinical outcome assessments (COAs) to evaluate physical function, as well as social and emotional well-being in clinical trials enrolling a pediatric population with achondroplasia. Qualitative interviews lasting up to 90 min were conducted in the US with children/adolescents with achondroplasia and/or their caregivers. Interviews utilized concept elicitation methodology to explore experiences and priorities for treatment outcomes. Cognitive debriefing methodology explored relevance and understanding of selected COAs. RESULTS: Interviews (N = 36) were conducted with caregivers of children age 0-2 years (n = 8) and 3-7 years (n = 7) and child/caregiver dyads with children age 8-11 years (n = 15) and 12-17 years (n = 6). Children/caregivers identified pain, short stature, impacts on physical functioning, and impacts on well-being (e.g. negative attention/comments) as key bothersome aspects of achondroplasia. Caregivers considered an increase in height (n = 9/14, 64%) and an improvement in limb proportion (n = 11/14, 71%) as successful treatment outcomes. The Childhood Health Assessment Questionnaire (CHAQ) and Quality of Life in Short Stature Youth (QoLISSY-Brief) were cognitively debriefed. CHAQ items evaluating activities, reaching, and hygiene were most relevant. QoLISSY-Brief items evaluating reaching, height bother, being treated differently, and height preventing doing things others could were most relevant. The CHAQ and QoLISSY-Brief instructions, item wording, response scales/options and recall period were well understood by caregivers and adolescents age 12-17. Some children aged 8-11 had difficulty reading, understanding, or required caregiver input. Feedback informed minor amendments to the CHAQ and the addition of a 7-day recall period to the QoLISSY-Brief. These amendments were subsequently reviewed and confirmed in N = 12 interviews with caregivers of children age 0-11 (n = 9) and adolescents age 12-17 (n = 3). CONCLUSIONS: Achondroplasia impacts physical functioning and emotional/social well-being. An increase in height and improvement in limb proportion are considered to be important treatment outcomes, but children/adolescents and their caregivers expect that a successful treatment should also improve important functional outcomes such as reach. The CHAQ (adapted for achondroplasia) and QoLISSY-Brief are relevant and appropriate measures of physical function and emotional/social well-being for pediatric achondroplasia trials; patient-report is recommended for age 12-17 years and caregiver-report is recommended for age 0-11 years.

An empirical tool for estimating the share of unmet need due to healthcare inefficiencies, suboptimal access, and lack of effective technologies.

BACKGROUND: Although there has been growing attention to the measurement of unmet need, which is the overall epidemiological burden of disease, current measures ignore the burden that could be eliminated from technological advances or more effective use of current technologies. METHODS: We developed a conceptual framework and empirical tool that separates unmet need from met need and subcategorizes the causes of unmet need into suboptimal access to and ineffective use of current technologies and lack of current technologies. Statistical models were used to model the relationship between health-related quality of life (HR-QOL) and treatment utilization using data from the National Health and Wellness Survey (NHWS). Predicted HR-QOL was combined with prevalence data from the Global Burden of Disease Study (GBD) to estimate met need and the causes of unmet need due to morbidity in the US and EU5 for five diseases: rheumatoid arthritis, breast cancer, Parkinson's disease, hepatitis C, and chronic obstructive pulmonary disease (COPD). RESULTS: HR-QOL was positively correlated with adherence to medication and patient-perceived quality and negatively correlated with financial barriers. Met need was substantial across all disease and regions, although significant unmet need remains. While the majority of unmet need was driven by lack of technologies rather than ineffective use of current technologies, there was considerable variation across diseases and regions. Overall unmet need was largest for COPD, which had the highest prevalence of all diseases in this study. CONCLUSION: We developed a methodology that can inform decisions about which diseases to invest in and whether those investments should focus on improving access to currently available technologies or inventing new technologies.

A cost-benefit analysis of smoking cessation prescription coverage from a US payer perspective.

INTRODUCTION: Smoking drives substantial direct health care spending, comprising 8.7% ($168 billion) of annual United States aggregated spending. Smoking cessation (SC) prescription use is an effective strategy to improve health outcomes, increase quit rates, and reduce economic burden. However, patient out-of-pocket costs may limit the use. Health care payers play a vital role in driving use through formulary decisions and copayment policies but must consider both the near-term financial investment as well as downstream effects of increased coverage on health care budgets. This study estimates the return on investment (ROI) of providing Affordable Care Act (ACA)-recommended prescription SC coverage. METHODS: A cost-benefit analysis (CBA) estimates the ROI of providing prescription SC coverage, based on pharmacy costs and savings from smoking-attributable medical expenditures among Medicare, Medicaid, and commercial plan enrollees over 10 years. The CBA incorporated national-level population demographics, smoking prevalence estimates, proportion of smokers attempting to quit, and the utilization of SC products. A five-state Markov chain model simulated patterns of quit attempts, relapse, and cessation assuming two quit attempts per year, no patient cost-sharing, and 25.4% utilization of prescription SC aids. Results include number of quitters, annual pharmacy and smoking-attributable medical costs, and ROI. RESULTS: After initial investment in SC treatment, smoking-attributable medical benefits accrue over time, generating a positive ROI by year 4 for commercial (11.3%) and Medicaid (78.4%) plans and by year 3 for Medicare (30.6%). Over 10 years, an average return of $1.18, $2.50, and $3.22 savings per dollar spent on SC prescriptions for commercial, Medicaid, and Medicare plans, respectively, may be realized. DISCUSSION: Given the proven efficacy of SC pharmacotherapy, near-term investments in supporting ACA-recommended SC coverage translate into a positive ROI. As smoking is a leading cause of morbidity and mortality, increased access to prescription SC medications may improve health outcomes and reduce smoking-attributable costs to payers over time.

Mobile App Usage Patterns of Patients Prescribed a Smoking Cessation Medicine: Prospective Observational Study.

BACKGROUND: Cigarette smoking is the leading preventable cause of death and is responsible for more than 480,000 deaths per year in the United States. Smoking cessation is challenging for many patients. Regardless of available treatment options, most quit attempts are unaided, and it takes multiple attempts before a patient is successful. With the ever-increasing use of smartphones, mobile apps hold promise in supporting cessation efforts. This study evaluates the ease of use and user satisfaction with the Pfizer Meds app to support smoking cessation among patients prescribed varenicline (Chantix). OBJECTIVE: Study participants included varenicline users who downloaded and used the app on their personal smartphone. The main objectives were to report mobile app download frequency and usage details and to describe the participant-reported satisfaction with and usefulness of the app over the 14-week follow-up study period. METHODS: Adults aged 18 years or older who had been prescribed varenicline were identified from the Express Scripts Incorporated pharmacy claims database. After meeting privacy restrictions, subjects were sent an invitation letter and second reminder letter with instructions on how to download the Pfizer Meds mobile app. Participants received a push notification to complete a smartphone-enabled survey regarding the utility of the app 12 weeks after downloading the app. Descriptive statistics summarized sociodemographics, use of varenicline, and details of use and satisfaction with the mobile app. RESULTS: Of the 38,129 varenicline users who were sent invitation letters, 1281 participants (3.35%) downloaded the Pfizer Meds app. Of the 1032 users with demographic and other data, 585 (56.68%) were females, and 446 (43.22%) were males; mean age was 46.4 years (SD 10.8). The mean number of app sessions per participant was 4.0 (SD 6.8). The end-of-study survey was completed by 131 survey respondents (10.23%, 131/1281); a large number of participants (117/131, 89.3%) reported being extremely, very, or moderately satisfied with the app. A total of 97 survey respondents (97/131, 74.0%) reported setting up a quit date in the app. Of those, 74 (74/97, 76%) reported quitting on their quit date. CONCLUSIONS: Positive patient engagement was observed in this study based on app download and usage. This study quantified how the Pfizer Meds app performed in an observational real-world data setting. The findings demonstrate the willingness of participants to set a quit date and use the app for support in medication adherence, refill reminders, and information regarding how to take the medication. This study provides real-world evidence of the contribution apps can make to the continued encouragement of smokers to improve their health by smoking cessation.

Smoking Cessation Is Associated With Lower Indirect Costs.

OBJECTIVE: This study quantified differences in indirect costs due to decreased work productivity between current and former smokers. Former smokers were further categorized by number of years since quitting to assess corresponding differences. METHODS: Data on employed individuals were obtained from the 2013 US National Health and Wellness Survey (NHWS; N = 75,000). Indirect costs were calculated for current smokers and former smokers from weekly wages based on age and sex. RESULTS: The annual total indirect costs for current smokers were $1327.53, $1560.18, and $1839.87 higher than for those who quit 0 to 4 years, 5 to 10 years, and more than or equal to 11 years prior, respectively. There were no significant differences in mean total indirect costs between the former smoker groups. CONCLUSIONS: Current smokers showed significantly higher total annual indirect costs compared with former smokers, independently of the number of years since quitting smoking.

A cost-effectiveness analysis of varenicline for smoking cessation using data from the EAGLES trial.

BACKGROUND: The cost-effectiveness of varenicline has been demonstrated in the US health care setting using the Benefits of Smoking Cessation on Outcomes (BENESCO) model to simulate the lifetime direct costs and consequences of a hypothetical cohort of US adult smokers who make a single attempt to quit. The aim of this study was to undertake an updated cost-effectiveness analysis, using current epidemiology inputs and recently published smoking cessation data from the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES), the largest clinical trial of smoking cessation pharmacotherapies conducted to date. METHODS: BENESCO is a Markov model simulating the effect of a single attempt to quit smoking on four smoking-related diseases: coronary heart disease, stroke, chronic obstructive lung disease, and lung cancer. Inputs were updated to include efficacy from EAGLES and newer data for the epidemiology of smoking in the US, the epidemiology and direct treatment costs of the four morbidities, and the costs of the interventions. Analyses compared varenicline, bupropion, nicotine replacement therapy (NRT) patch, and placebo with regard to the incidence of smoking-related morbidity, the incidence of smoking-related mortality, and cost-effectiveness at a time horizon from 2 years to lifetime. RESULTS: The study cohort comprised of 18,394,068 US adult smokers who made a single quit attempt during the first year of the model. For varenicline, there were an estimated 319,730 fewer smoking-related morbidities at the lifetime compared with placebo. Similarly, smoking-related mortality decreased by 198,240 subjects when varenicline was compared with placebo. For the same time horizon, varenicline was more effective and less costly, ie, dominant, compared with all comparators in the cost-effectiveness analysis. CONCLUSION: Based on the BENESCO model, smoking cessation with varenicline results in reduced incidence of smoking-related morbidity and mortality compared with other smoking cessation interventions and remains a cost-effective strategy in the US population.

Estimating the public economic consequences of introducing varenicline smoking cessation therapy in South Korea using a fiscal analytic framework.

BACKGROUND AND AIMS: Smoking gives rise to many cross-sectorial public costs and benefits for government. Costs arise from increased healthcare spending and work-related social benefits, while smoking itself provides significant revenue for government from tobacco taxes. To better understand the public economic impact of smoking and smoking cessation therapies, this study developed a government perspective framework for assessing smoking-attributable morbidity and mortality and associated public costs. This framework includes changes in lifetime tax revenue and health costs, as well as changes in tobacco tax revenue, from fewer smokers. METHODS: A modified generational accounting framework was developed to assess relationships between smoking-attributable morbidity and mortality and public economic consequences of smoking, including lifetime tax revenue gains/losses, government social transfers, and health spending. Based on the current prevalence of smoking in South Korean males, a cohort model was developed for smokers, former-smokers, and never-smokers. The model simulated the lifetime discounted fiscal transfers for different age cohorts in 5 year age bands, and the return on investment (ROI) from smoking cessation therapy. RESULTS: Former smokers are estimated to generate higher lifetime earnings and direct tax revenues and lower lifetime healthcare costs due to the reduction of smoking-attributable mortality and morbidity compared to smokers, even after accounting for reduced tobacco taxes paid. Based on the costs of public investments in varenicline, this study estimated a ROI from 1.4-1.7, depending on treatment age, with higher ROI in younger cohorts, with an average ROI of 1.6 for those aged less than 65. CONCLUSIONS: This analysis suggests that reductions in smoking can generate positive public economic benefits for government, even after accounting for lost tobacco tax revenues. The results described here are likely applicable to countries having similar underlying smoking prevalence, comparable taxation rates, and social benefit protection provided to individuals with smoking-related conditions.

Content Validity of a Willingness to Quit Tool for Use with Current Smokers in Clinical Practice.

INTRODUCTION: Despite reductions in rates of smoking in the past decade, smoking remains one of the most significant public health concerns. Quitting smoking can result in reductions in a number of serious health conditions. The brief Willingness to Quit (WTQ) tool can be used in routine clinical practice to assess current willingness to quit and engage a patient-physician dialogue regarding smoking cessation. The overall aim of this study was to validate the content of a WTQ tool for use with current smokers in clinical practice. METHODS: In-depth, qualitative interviews were conducted with 12 current smokers and five physicians. The interview was divided into two sections: concept elicitation (CE) followed by cognitive debriefing (CD). During CE, participants were asked questions exploring the different factors that can impact an individual's willingness to quit smoking. During CD, participants were given a copy of the WTQ tool and asked to comment on their level of understanding and interpretability of the items and the feasibility of completing the tool in clinical practice. RESULTS: All of the current smokers (n = 12) and physicians (n = 5) interviewed indicated that the items were understandable and relevant to assess willingness to quit. The tool was considered simple and suitable for use in clinical practice. CONCLUSION: The WTQ tool is a brief tool to assess willingness to quit and to engage communication between patients and physicians. All smokers should be offered smoking cessation support and facilitating a discussion on willingness to quit further supports a personalized quit plan. FUNDING: Pfizer Inc.

Characteristics of first-time varenicline users - A cross-sectional study in Finnish quitters.

BACKGROUND: Varenicline is an efficacious medicine for smoking cessation (SC) but little is known about the characteristics of varenicline users. This study examined the characteristics of first-time (naïve) varenicline users in Finland and compared those who had previously used SC pharmacotherapy to those who were trying SC pharmacotherapy for the first time. METHODS: A cross-sectional survey was conducted in Finnish community pharmacies between February 2014 and January 2015. Pharmacy customers purchasing a varenicline starter package for the first time ever were asked to complete a questionnaire or to participate in a structured interview conducted by the pharmacist (identical questions). The questionnaire included questions about demographic characteristics, smoking habits, previous cessation attempts and factors associated with varenicline use. RESULTS: Altogether 98 people completed the survey. The majority were daily smokers (96%, n = 94), with a history of over 10 years of regular smoking (94%, n = 92), and a strong/very strong nicotine dependence (67%, n = 66). Half of the participants (54%, n = 53) were trying a SC pharmacotherapy for the first time. Demographic characteristics and smoking habits were similar between first-time and previous users of SC medications (p > 0.05). Health centers (42%, n = 41) and occupational health care clinics (37%, n = 36) were the most common sources of varenicline prescriptions. The majority of participants received the prescription for varenicline after mentioning their desire for quitting to a physician (70%, n = 69). CONCLUSIONS: Considering the relatively large proportion of SC naïve medicine users among new users of varenicline, smokers who have previously been reluctant to quit smoking, to use other pharmacological SC interventions, or perhaps unaware of these options may be interested in attempting cessation with varenicline. Most participants made the initiative to discuss their smoking with the physician, which led to varenicline prescribing. This suggests that physicians may not satisfactorily recognize their patients' nicotine dependence and desire to quit, and they should more actively support patients' smoking cessation.

Benefits of quitting smoking on work productivity and activity impairment in the United States, the European Union and China.

BACKGROUND: Smoking has important health and economic consequences for individuals and society. This study expands the understanding of work-related burden associated with smoking and benefit of smoking cessation across the US, European Union (EU) and China using large-scale, representative survey methodology. METHODS: Data utilised the 2013 National Health and Wellness Survey in United States (US), EU5 (UK, France, Germany, Italy, and Spain) and China. Working-aged respondents 18-64 were used in the analyses (US N=58 500; EU5 N=50 417; China N=17 987) and were categorised into: current smokers, trying to quit, former smokers and never smokers. Generalised linear models controlling for demographics and health characteristics examined the relationship of smoking status with work productivity and activity impairment (WPAI-GH). The WPAI-GH measures were: absenteeism, presenteeism, overall work impairment, and activity impairment. Separately, current smokers were compared with those who quit 0-4, 5-10 and 11 or more years ago on WPAI-GH end-points. RESULTS: Current smokers reported greater absenteeism in the US and China and greater presenteeism, overall work impairment, and activity impairment than former and never smokers across the three regions. Those who quit even 0-4 years ago demonstrated lower absenteeism, presenteeism, and activity impairment in China and lower presenteeism, overall work impairment, and activity impairment in the US and EU5. CONCLUSIONS: Smoking was associated with significant work productivity loss in the US, EU5 and China. The results suggest that quitting benefits extend to work productivity rapidly after cessation, serving to further encourage and promote the implementation of workplace cessation programs.

Estimated Budget Impact of Adopting the Affordable Care Act's Required Smoking Cessation Coverage on United States Healthcare Payers.

INTRODUCTION: Despite abundant information on the negative impacts of smoking, more than 40 million adult Americans continue to smoke. The Affordable Care Act (ACA) requires tobacco cessation as a preventive service with no patient cost share for all FDA-approved cessation medications. Health plans have a vital role in supporting smoking cessation by managing medication access, but uncertainty remains on the gaps between smoking cessation requirements and what is actually occurring in practice. This study presents current cessation patterns, real-world drug costs and plan benefit design data, and estimates the 1- to 5-year pharmacy budget impact of providing ACA-required coverage for smoking cessation products to understand the fiscal impact to a US healthcare plan. METHODS: A closed cohort budget impact model was developed in Microsoft Excel® to estimate current and projected costs for US payers (commercial, Medicare, Medicaid) covering smoking cessation medicines, with assumptions for coverage and smoking cessation product utilization based on current, real-world national and state-level trends for hypothetical commercial, Medicare, and Medicaid plans with 1 million covered lives. A Markov methodology with five health states captures quit attempt and relapse patterns. Results include the number of smokers attempting to quit, number of successful quitters, annual costs, and cost per-member per-month (PMPM). RESULTS: The projected PMPM cost of providing coverage for smoking cessation medications is $0.10 for commercial, $0.06 for Medicare, and $0.07 for Medicaid plans, reflecting a low incremental PMPM impact of covering two attempts ranging from $0.01 for Medicaid to $0.02 for commercial and Medicare payers. CONCLUSION: The projected PMPM impact of covering two quit attempts with access to all seven cessation medications at no patient cost share remains low. Results of this study reinforce that the impact of adopting the ACA requirements for smoking cessation coverage will have a limited near-term impact on health plan's budgets. FUNDING: Pfizer Inc.

A Pragmatic Randomized Trial Comparing Telephone-Based Enhanced Pharmacy Care and Usual Care to Support Smoking Cessation.

BACKGROUND: Smoking is the leading preventable cause of death, and tobacco control professionals continue to make progress in cessation efforts. Pharmacists can assist smokers seeking to quit by offering counseling on smoking cessation pharmacotherapies. Pragmatic randomized trials are useful for investigating practical questions about an intervention's risks, benefits, and costs in routine clinical practice. OBJECTIVE: To evaluate an enhanced pharmacy care (EPC) program involving personalized pharmacist-provided telephone counseling for supporting prescription smoking cessation medications compared with usual care (UC). METHODS: Cigarette smokers filling a newly prescribed smoking cessation pharmacotherapy and with pharmacy benefits managed by Express Scripts were recruited. Qualified subjects were randomized 1:1 to EPC and UC. Subjects in EPC received 3 telephone-counseling sessions from specialist pharmacists during the early course of the study, while subjects in UC did not receive any counseling sessions. Study outcomes were collected through telephone contact and using the Express Scripts prescription database. The primary outcome assessed the 1-week point prevalence (PP) of smoking abstinence at the end of the trial (week 12). Secondary outcomes included 4-week PP at week 12 and adherence, evaluated by proportion of days covered (PDC), to prescribed smoking cessation pharmacotherapies. RESULTS: There were 1,017 randomized subjects. Among them, 1,002 subjects were included in the analysis, and 513 were randomized into EPC and 489 into UC. Baseline demographics, smoking history, and prescribed smoking cessation pharmacotherapies were comparable. Varenicline and nicotine replacement therapy (NRT) were most frequently prescribed for smoking cessation. In EPC, 46.0% received all 3 counseling sessions; 29.4% received 2 sessions; and 14.6% received 1 session. Overall, 353 subjects in EPC and 383 subjects in UC completed the week 12 assessment. In the analysis for 1-week PP of smoking abstinence at week 12, the percentage of abstainers in EPC was numerically higher than in UC (42.3% vs. 38.2%) with OR = 1.24, 95% CI = 0.96-1.61. It was not statistically significant. Adherence to prescription smoking cessation medication was significantly higher in EPC versus UC (49.7% vs. 45.6%; P = 0.033). CONCLUSIONS: This study evaluated whether a telephone-based pharmacy care program, provided by pharmacists and designed to support attempted quitters, improved quitting and increased adherence over usual care. The findings suggest that an enhanced program may benefit smokers by increasing prescription smoking cessation medication adherence. Future research should explore this program's effect on smokers who are compliant, based on insights on quitting provided by the post hoc analyses and limitations of the current study design. DISCLOSURES: This study was sponsored by Pfizer. Gong, Baker, Zou, Bruno, Jumadilova, and Lawrence are employees and stockholders of Pfizer. Wilson and Ewel are employees of United BioSource Corporation, which received funding from Pfizer for conducting this study and for the development of this manuscript. Study concept and design were contributed by Gong, Bruno, and Ewel, with assistance from Jumadilova, Lawrence, and Zou. Gong, Jumadilova, Lawrence, and Ewel collected the data. Data interpretation was performed by Baker, Zou, and Wilson, assisted by Gong, Lawrence, and Ewel. The manuscript was written by Baker, Ewel, and Gong, with assistance from the other authors, and revised by Baker, Wilson, Zou, and Gong, with assistance from Bruno and Jumadilova.

COPD exacerbations associated with the modified Medical Research Council scale and COPD assessment test among Humana Medicare members.

BACKGROUND: The Global initiative for chronic Obstructive Lung Disease guidelines recommend assessment of COPD severity, which includes symptomatology using the modified Medical Research Council (mMRC) or COPD assessment test (CAT) score in addition to the degree of airflow obstruction and exacerbation history. While there is great interest in incorporating symptomatology, little is known about how patient reported symptoms are associated with future exacerbations and exacerbation-related costs. METHODS: The mMRC and CAT were mailed to a randomly selected sample of 4,000 Medicare members aged >40 years, diagnosed with COPD (≥2 encounters with International Classification of Dis eases-9th Edition Clinical Modification: 491.xx, 492.xx, 496.xx, ≥30 days apart). The exacerbations and exacerbation-related costs were collected from claims data during 365-day post-survey after exclusion of members lost to follow-up or with cancer, organ transplant, or pregnancy. A logistic regression model estimated the predictive value of exacerbation history and symptomatology on exacerbations during follow-up, and a generalized linear model with log link and gamma distribution estimated the predictive value of exacerbation history and symptomatology on exacerbation-related costs. RESULTS: Among a total of 1,159 members who returned the survey, a 66% (765) completion rate was observed. Mean (standard deviation) age among survey completers was 72.0 (8.3), 53.7% female and 91.2% white. Odds ratios for having post-index exacerbations were 3.06, 4.55, and 16.28 times for members with 1, 2, and ≥3 pre-index exacerbations, respectively, relative to members with 0 pre-index exacerbations (P<0.001 for all). The odds ratio for high vs low symptoms using CAT was 2.51 (P<0.001). Similarly, exacerbation-related costs were 73% higher with each incremental pre-index exacerbation, and over four fold higher for high-vs low-symptom patients using CAT (each P<0.001). The symptoms using mMRC were not statistically significant in either model (P>0.10). CONCLUSION: The patient-reported symptoms contribute important information related to future COPD exacerbations and exacerbation-related costs beyond that explained by exacerbation history.

Risk assessment of readmissions following an initial COPD-related hospitalization.

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a leading cause of hospitalizations and readmissions in the US. Reducing the frequency of hospital readmission is a high priority of US health care organizations and government agencies. This study evaluated the risk factors associated with readmissions among commercially insured adults aged 40-65 years in the US who were hospitalized for COPD. METHODS: This retrospective cohort study used anonymized claims data from the Truven Health MarketScan® Commercial Claims and Encounters database. The patients included were aged 40-65 years, had an index hospitalization with a primary diagnosis of COPD between July 1, 2008 and June 30, 2010 (continuously enrolled 12 months before and after), and were alive at hospital discharge. Patients with cystic fibrosis or tuberculosis or who were transferred to another inpatient facility after hospital discharge were excluded. All readmissions regardless of diagnosis, and separately a subset of all readmissions that had COPD as a primary or secondary diagnosis (COPD-related), were examined. Univariate descriptive statistics and multivariable regression methods were used. RESULTS: Of the 18,568 patients with index COPD hospitalizations, 6,095 (32.83%) met the eligibility criteria. Of those, 503 (8.25%) were readmitted within the first 30 days post-index hospitalization and 2,527 (41.46%) within the first year (COPD-related 340 [5.58%] and 1,681 [27.58%], respectively). The median time to the first readmission post initial discharge was 4.0 months, with a mean of 5.0 ± 3.4 months. Multivariable regression analyses showed that comorbid conditions and health care utilization in the pre-index period were significant predictors for readmission both 30 and 90 days following index hospitalization. CONCLUSION: A relatively high readmission rate was observed for patients aged 40-65 years. The results suggest that attention to patient comorbidities and pre-index/index health care service utilization may help identify hospitalized COPD patients at higher risk for readmission.

The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene.

Lynch syndrome is characterized by mutations in one of four mismatch repair genes, MLH1, MSH2, MSH6, or PMS2. Clinical mutation analysis of these genes includes sequencing of exonic regions and deletion/duplication analysis. However, detection of deletions and duplications in PMS2 has previously been confined to Exons 1-11 due to gene conversion between PMS2 and the pseudogene PMS2CL in the remaining 3' exons (Exons 12-15). We have recently described an MLPA-based method that permits detection of deletions of PMS2 Exons 12-15; however, the frequency of such deletions has not yet been determined. To address this question, we tested for 3' deletions in 58 samples that were reported to be negative for PMS2 mutations using previously available methods. All samples were from individuals whose tumors exhibited loss of PMS2 immunohistochemical staining without concomitant loss of MLH1 immunostaining. We identified seven samples in this cohort with deletions in the 3' region of PMS2, including three previously reported samples with deletions of Exons 13-15 (two samples) and Exons 14-15. Also detected were deletions of Exons 12-15, Exon 13, and Exon 14 (two samples). Breakpoint analysis of the intragenic deletions suggests they occurred through Alu-mediated recombination. Our results indicate that ∼12% of samples suspected of harboring a PMS2 mutation based on immunohistochemical staining, for which mutations have not yet been identified, would benefit from testing using the new methodology.

National Ambulatory Medical Care Survey: tobacco intervention practices in outpatient clinics.

Tobacco use remains the leading cause of preventable death. The outpatient medical clinic represents an important venue for delivering evidence-based interventions to large numbers of tobacco users. Extensive evidence supports the effectiveness of brief interventions. In a retrospective database analysis of 11,827 adult patients captured in the 2005 National Ambulatory Medical Care Survey (of which 2,420 were tobacco users), we examined the degree to which a variety of patient demographic, clinical and physician-related variables predict the delivery of tobacco counseling during a routine outpatient visit in primary care settings. In 2005, 21.7% of identified tobacco users received a tobacco intervention during their visit. The probability of receiving an intervention differed by gender, geographic region and source of payment. Individuals presenting with tobacco-related health conditions were more likely to receive an intervention. Most physicians classified as specialists were less likely to intervene. The provision of tobacco intervention services appears to be increasing at a modest rate, but remains well below desirable levels. It is a priority that brief interventions be routinely implemented to reduce the societal burden of tobacco use.

Changes in health-related quality of life with smoking cessation treatment.

BACKGROUND: Cigarette smoking causes reduced health-related quality of life (QoL) and smoking abstinence improves health-related QoL. We assessed the effects of treatment for tobacco dependence on the health-related QoL in a 52-week randomized controlled trial of varenicline and bupropion sustained release (SR). METHODS: Subjects who smoked ≥10 cigarettes per day for the past year were randomly assigned to receive varenicline 1 mg twice daily (n = 696), bupropion SR 150 mg twice daily (n = 671) or placebo (n = 685) for 12 weeks and followed post-therapy for an additional 40 weeks. Health-related QoL was assessed using the Smoking Cessation Quality of Life questionnaire at baseline and Weeks 12, 24 and 52. RESULTS: Health transition (perceived health compared with baseline) and self-control were both significantly improved among subjects receiving varenicline and bupropion SR compared with placebo at Weeks 12, 24 and 52. Similarly, varenicline-treated subjects had significantly improved health transition and self-control compared with subjects who received bupropion SR at Weeks 12 and 24, and at Week 52 for health transition. A significant positive association existed between length of continuous abstinence and improved health transition, vitality, self-control, anxiety and overall mental profile. In most instances both a direct and an indirect effect (through continuous smoking abstinence) of each active treatment (vs. placebo) contributed to improved self-control and health transition. CONCLUSION: Treatment with varenicline and bupropion SR for smoking cessation resulted in improved self-control and health transition that was mediated in large part by continuous smoking abstinence.

A PIK3CA pyrosequencing-based assay that excludes pseudogene interference.

Phosphatidylinositol 3'-kinase gene (PIK3CA) encodes a lipid kinase that regulates signaling pathways downstream of epidermal growth factor receptor and is mutated in 10% to 30% of colorectal cancers. Activating mutations in this gene up-regulates the AKT signaling pathway, making it a potentially useful therapeutic target. Mutations in PIK3CA are not exclusive of mutations in KRAS, BRAF, or NRAS. We designed a pyrosequencing assay to detect mutations in all three positions of codons 542 and 545 in exon 9 and codon 1047 in exon 20 of this gene. The exon 9 reverse PCR primer was designed to avoid amplifying a pseudogene in chromosome 22 that has >95% homology with exons 9 through 13 in PIK3CA. Two hundred colorectal cancers from FFPE tissue previously characterized for KRAS mutation status were evaluated for PIK3CA mutations. In KRAS-mutated samples, 20% had an additional mutation in PIK3CA. The mutation rate in KRAS wild-type samples was 7.5%. When using our assay, pseudogene was not observed in any of these samples. In addition, pseudogene- and gene-specific amplification was performed on DNA from 40 additional colorectal cancers. Sequencing of these PCR products yielded the expected gene or pseudogene sequence in all cases. Thus, we have developed a PIK3CA pyrosequencing assay capable of detecting mutations in all three positions in the three hot spot codons with no pseudogene interference.

FOXL2 mutation and large-scale genomic imbalances in adult granulosa cell tumors of the ovary.

Adult granulosa cell tumors (AGCTs) are a rare class of ovarian tumors with recurrent cytogenetic abnormalities including trisomy 12, trisomy 14, monosomy 16/deletion 16q, and monosomy 22. Over 90% contain a missense point mutation (C134W) in the FOXL2 gene at 3q22.3. The relationship between FOXL2 mutation and cytogenetic abnormalities is unclear, although both are presumably early events in tumorigenesis. In addition, FOXL2 C134W mutant allele imbalance has been noted in a minority of AGCTs, but the mechanism for allelic imbalance has not yet been described. We used a microarray platform designed for formalin-fixed, paraffin-embedded (FFPE) tissue specimens, the Affymetrix OncoScan FFPE Express 330K Molecular Inversion Probe (MIP) array, to explore the correlation between genomic imbalances detected by microarray and FOXL2 mutation status detected by pyrosequencing in a series of 21 archived AGCTs. Tumors were characterized by histopathologic features, stage, and alpha-inhibin expression by immunohistochemistry. All tumors were positive for inhibin, and 18/21 tumors contained a FOXL2 mutation. The most common genomic imbalances were a gain of 14q, a loss of 16q, and a loss of 22q. Three tumors showed evidence of FOXL2 mutant allele imbalance by pyrosequencing; microarray revealed a 32.5 Mb deletion encompassing FOXL2 in 1 case and a 70.9 Mb stretch of homozygosity encompassing FOXL2 in the other case. The third case, with a FOXL2 mutant allele imbalance, showed a diminished mutant allele population (32%) despite high estimated tumor content (>90%), suggesting tumor heterogeneity for the mutation. This study provides the first correlation of FOXL2 mutation status and genomic imbalances in AGCTs, and it further elucidates the mechanisms for mutant allele imbalance in cancer.

Examining web equivalence and risk factor sensitivity of the COPD population screener.

OBJECTIVES: The primary aim was to assess the equivalence of an Internet-based chronic obstructive pulmonary disease-population screener (COPD-PS) relative to a validated paper-and-pencil version. A secondary aim was to compare groups based on known COPD risk factors, such as smoking status and gender. METHODS: Using an online panel survey organization, participants were randomized to internet or paper-and-pencil assessment where they completed the COPD-PS and other study forms. A subset of respondents also completed a test-retest reliability assessment. Finally, several thousand additional online respondents completed the COPD-PS for risk factor analyses. RESULTS: A total of 1006 adults completed the randomized study (N = 504 online, N = 502 by mail). There were no differences between the arms in mean COPD-PS scores (mean difference: 0.12; 95% confidence interval: -0.14-+0.37; P = 0.365). In the web arm, 106/504 (21.0%) exceeded the screening cut-off compared to 101/502 (20.1%) in the paper-administration arm (difference in proportions: 0.9%; 95% confidence interval: -4.1%-+5.9%; P = 0.720). Subgroup analyses on a separate cohort of 3001 adults demonstrated hypothesized differences between groups defined by smoking status, presence of COPD, and shortness of breath. CONCLUSION: The methods of administration that were evaluated in this study (internet vs. paper and pencil) resulted in no significant differences in COPD-PS mean scores. Furthermore, the predictive utility of the COPD-PS was not different between methods of administration, even after accounting for age and smoking status.