Use of a historical control group in a noninferiority trial assessing a new antibacterial treatment: A case study and discussion of practical implementation aspects.

When recruitment into a clinical trial is limited due to rarity of the disease of interest, or when recruitment to the control arm is limited due to ethical reasons (eg, pediatric studies or important unmet medical need), exploiting historical controls to augment the prospectively collected database can be an attractive option. Statistical methods for combining historical data with randomized data, while accounting for the incompatibility between the two, have been recently proposed and remain an active field of research. The current literature is lacking a rigorous comparison between methods but also guidelines about their use in practice. In this paper, we compare the existing methods based on a confirmatory phase III study design exercise done for a new antibacterial therapy with a binary endpoint and a single historical dataset. A procedure to assess the relative performance of the different methods for borrowing information from historical control data is proposed, and practical questions related to the selection and implementation of methods are discussed. Based on our examination, we found that the methods have a comparable performance, but we recommend the robust mixture prior for its ease of implementation.

HFE p.C282Y homozygosity predisposes to rapid serum ferritin rise after menopause: A genotype-stratified cohort study of hemochromatosis in Australian women.

BACKGROUND AND AIM: Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations (HFE wild types) as comparison groups. METHODS: A sample of the Melbourne Collaborative Cohort Study was selected for the "HealthIron" study (n = 1438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing. RESULTS: For p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), P < 0.001) during the first 10 years postmenopause, after which SF continued to increase but at less than half the previous rate. In contrast, SF profiles for other HFE genotype groups increase more gradually and did not show a distinction between premenopausal and postmenopausal SF levels. Only p.C282Y homozygotes had predicted SF exceeding 200 µg/L postmenopause, but the projected SF did not increase the risk of iron overload-related disease. CONCLUSIONS: These data provide the first documented evidence that physiological blood loss is a major factor in determining the marked gender difference in expression of p.C282Y homozygosity.

Durability of Response in Children Treated With Pegylated Interferon alfa [corrected] 2a ± Ribavirin for Chronic Hepatitis C.

OBJECTIVES: No long-term data have been published on the durability of response following pegylated interferon (PegIFN) treatment in children with chronic hepatitis C. This prospective, multicenter, long-term follow-up (LTFU) study aimed to assess long-term durability of sustained virological response (SVR), long-term safety and tolerability, and the association between IL28B genotype and treatment response, in children previously treated with PegIFN alfa-2a ± ribavirin (RBV) in the PEDS-C trial. METHODS: A total of 93 patients were assessed for enrollment, and 38 enrolled in the study. Patients attended 2 study visits: 5 (mean 5.6, range 4.1-6.6) and 6 (6.6, 5.1-7.7) years after treatment cessation. Standardized medical history, physical examination, and laboratory testing were performed at these visits. Reminder telephone calls were conducted at 4 and 8 months after the initial visit. RESULTS: The LTFU cohort was the representative of the original PEDS-C cohort because both baseline and treatment characteristics were comparable. Of the 38 participants, 21 achieved SVR (responders) during the PEDS-C trial and 17 had not (nonresponders). All 21 responders maintained undetectable hepatitis C virus RNA during the LTFU (4.4-7.0 years after achieving SVR) in contrast to the nonresponders who demonstrated persistent viremia. IL28B CC genotype was associated with SVR (67% vs 30% in non-CC, P = 0.028). CONCLUSION: Long-term durability of SVR is excellent following PegIFN alfa-2a treatment in children with chronic hepatitis C; SVR is higher in those with IL28B CC versus non-CC.

Long-term growth outcomes in children treated for chronic hepatitis C.

Effects on linear growth were noted in children treated with peginterferon ± ribavirin in the Pediatric Study of Hepatitis C trial. Growth was further examined in a subset of patients followed for up to 6 years post-treatment. No long-term effects on height-for-age z scores were observed that could be attributed to hepatitis C virus treatment.

Agenda-setting effects of sun-related news coverage on public attitudes and beliefs about tanning and skin cancer.

The topics and framing of news stories relevant to skin cancer prevention have shifted over time. This study examined agenda-setting effects of such news stories on public attitudes and beliefs about tanning and skin cancer. Content analysis data on 516 articles published in two major daily newspapers in Melbourne, Australia, from 1994 to 2007 were combined with circulation data to generate indices of potential news exposure. Associations between these indices and cross-sectional telephone survey data from the same period on 6,244 adults' tanning attitudes and perceived susceptibility to skin cancer were examined using logistic regression models, accounting for the temporal precedence of news content. Pro-sun protection stories on attitudes and behavior were associated with older adults not thinking a tan looks healthy. Pro-sun protection stories on solaria were associated with less preference for a deep tan among young adults who like to suntan. Stories on vitamin D that were unsupportive of or ambiguous about sun protection were associated with a number of pro-tan attitudes among younger adults. Results indicate news coverage during 1994-2007 served an important agenda-setting role in explaining the public's attitudes and beliefs about tanning and skin cancer. Vitamin D stories appeared most influential, particularly among young adults.

Smokers' responses to television advertisements about the serious harms of tobacco use: pre-testing results from 10 low- to middle-income countries.

BACKGROUND: While television advertisements (ads) that communicate the serious harms of smoking are effective in prompting quitting-related thoughts and actions, little research has been conducted among smokers in low- to middle-income countries to guide public education efforts. METHOD: 2399 smokers aged 18-34 years in 10 low- to middle-income countries (Bangladesh, China, Egypt, India, Indonesia, Mexico, Philippines, Russia, Turkey and Vietnam) viewed and individually rated the same five anti-smoking ads on a standard questionnaire and then engaged in a structured group discussion about each ad. Multivariate logistic regression analysis, with robust SEs to account for the same individual rating multiple ads, was performed to compare outcomes (message acceptance, perceived personalised effectiveness, feel uncomfortable, likelihood of discussing the ad) across ads and countries, adjusting for covariates. Ads by country interactions were examined to assess consistency of ratings across countries. RESULTS: Three ads with graphic imagery performed consistently highly across all countries. Two of these ads showed diseased human tissue or body parts, and a third used a disgust-provoking metaphor to demonstrate tar accumulation in smokers' lungs. A personal testimonial ad performed more variably, as many smokers did not appreciate that the featured woman's lung cancer was due to smoking or that her altered physical appearance was due to chemotherapy. An ad using a visual metaphor for lung disease was also more variable, mostly due to lack of understanding of the term 'emphysema'. CONCLUSION: Television ads that graphically communicate the serious harms of tobacco use are likely to be effective with smokers in low- to middle-income countries and can be readily translated and adapted for local use. Ads with complex medical terms or metaphors, or those that feature personal testimonials, are more variable and at least require more careful pre-testing and adaptation to maximise their potential.

Potential effectiveness of specific anti-smoking mass media advertisements among Australian Indigenous smokers.

Aboriginal and Torres Strait Islander Australians (Indigenous Australians) have more than twice the smoking prevalence of non-Indigenous Australians. Anti-smoking campaigns have demonstrated success in the general population but little is known about their impact among Indigenous people. A total of 143 Indigenous and a comparison group of 156 non-Indigenous smokers from South Australia were shown 10 anti-smoking advertisements representing a range of advertisements typically aired in Australia. Participants rated advertisements on a five-point Likert scale assessing factors including message acceptance and personalized effectiveness. On average, Indigenous people rated the mainstream advertisements higher than non-Indigenous people and were more likely to report that they provided new information. Advertisements with strong graphic imagery depicting the health effects of smoking were rated highest by Indigenous smokers. Advertisements featuring real people describing the serious health consequences of smoking received mixed responses. Those featuring an ill person were rated higher by Indigenous people than those featuring the family of the person affected by a smoking-related disease. With limited Indigenous-specific messages available and given the finite resources of most public health campaigns, exposure to mainstream strong graphic and emotive first-person narratives about the health effects of smoking are likely to be highly motivating for Indigenous smokers.

Sensitivity and specificity of the Distress Impact Thermometer for the detection of psychological distress among CRC survivors.

This study assessed the relative screening performance of the Distress Impact Thermometer (DIT) and cutoff levels with the established clinical case threshold of the Hospital Anxiety and Depression Scale (HADS) among a sample of colorectal cancer (CRC) survivors. Fifty-nine CRC survivors completed the DIT, HADS, and provided demographic information at baseline, and 45 of these patients completed the same measures at follow-up, giving a total of 104 participant data. Receiver operating characteristic (ROC) analysis was performed to determine the accuracy of the DIT compared to the HADS, with a cutoff score ≥8 on each HADS subscale (depression and anxiety) and ≥15 on the HADS total scale used to identify patients with psychological distress. The sample comprised slightly more males (63%) than females, with an average age of 59 years (SD = 9.53) and ranging from 33 to 77 years. The optimum DT cutoff score of ≥5 yielded a sensitivity of 60% and specificity of 86.1%; the area under the curve was 0.771 (95% confidence interval [CI] [0.646, 0.896]). For the depression subscale, the DT performed better on specificity than sensitivity, however the opposite was true for the anxiety subscale. The addition of an impact thermometer did not enhance screening performance. The results of this study provide support for a DT score of ≥5 for detecting psychological distress among CRC survivors and do not support the addition of an impact thermometer. The use of the DT might underestimate depression but overestimate anxiety.

Secondhand smoke drift: examining the influence of indoor smoking bans on indoor and outdoor air quality at pubs and bars.

INTRODUCTION: This study aimed to examine the influence of indoor smoking bans on indoor and outdoor air quality at pubs and bars and to assess whether secondhand tobacco smoke (SHS) drifts from outdoor smoking areas to adjacent indoor areas. METHODS: Data were covertly collected from a convenience sample of 19 pubs and bars that had at least 1 indoor area with an adjacent semi-enclosed outdoor eating/drinking area. Using TSI SidePak Personal Aerosol Monitors, concentrations of SHS (PM(2.5)) were measured concurrently in indoor and outdoor areas before and after implementation of the indoor smoking ban. Information was collected about the number of patrons and lit cigarettes and about the enclosure of outdoor areas. RESULTS: Indoor PM(2.5) concentrations reduced by 65.5% from pre-ban to post-ban (95% CI 32.6%-82.3%, p = .004). Outdoor exposure to PM(2.5) also reduced from pre-ban to post-ban by 38.8% (95% CI 3.2%-61.3%, p = .037). At post-ban, indoor concentrations of PM(2.5) were positively associated with outdoor concentrations. After adjustment for covariates, a 100% increase in geometric mean (GM) outdoor PM(2.5) was associated with a 36.1% (95% CI 2.4%-80.9%) increase in GM indoor PM(2.5) exposure (p = .035). DISCUSSION: Indoor smoking bans are an effective means of improving indoor and outdoor air quality in pubs and bars, although the air quality of smoke-free indoor areas may be compromised by smoking in adjacent outdoor areas. These findings require consideration in efforts to ensure adequate protection of the health of employees and patrons at hospitality venues.

Cardiovascular Safety of Tocilizumab Versus Etanercept in Rheumatoid Arthritis: A Randomized Controlled Trial.

OBJECTIVE: To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept. METHODS: This randomized, open-label, parallel-group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open-label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group. RESULTS: By week 4 of treatment, the serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow-up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77-1.43). Results were similar in sensitivity analyses and in the on-treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation. CONCLUSION: The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non-CV safety of tocilizumab.

Reperfusion and Clinical Outcomes in Acute Ischemic Stroke: Systematic Review and Meta-Analysis of the Stent-Retriever-Based, Early Window Endovascular Stroke Trials.

OBJECTIVE: To explore the effects of reperfusion grade rates on clinical outcomes in the setting of stent-retriever-based reperfusion therapy for anterior circulation stroke in early time windows. METHODS: Systematic searching of Medline and Embase databases was performed to identify stroke trials of stent-retriever-based therapy versus standard care. Mixed effects meta-regression was used to analyze the trial-level association between reperfusion rates and clinical outcomes. RESULTS: A total of five trials met the inclusion criteria (n = 1,287). Rates of successful reperfusion [modified thrombolysis in cerebral ischemia grade 2b/3] demonstrated strong evidence for an association with good functional outcomes [modified Rankin scale score (mRS) 0-2] OR 1.59 (95% CI 1.16, 2.19) p = 0.019 and very strong evidence for an association with excellent functional outcomes (mRS 0-1) OR 2.10 (95% CI 1.46, 3.01) p = 0.007. In addition, there was weak evidence for an association with symptomatic intracranial hemorrhage OR 0.54 (95% CI 0.28, 1.04) p = 0.057 and mortality OR 0.69 (95% CI 0.69, 1.01) p = 0.053. CONCLUSION: In early, stent-retriever-based acute ischemic stroke treatment, reperfusion appears to be a major predictor of outcomes. Every 10% increase in the rates of successful reperfusion is associated with an 11% increase in the probability of achieving good and 17% increase in the probability of achieving excellent outcomes. Symptomatic intracranial hemorrhage and mortality may be decreased as reperfusion rates are improved.

Comparing Handheld Meters and Electronic Dosimeters for Measuring Ultraviolet Levels under Shade and in the Sun.

This study aimed to compare the validity, reliability and practicality of alternative portable methods for measuring erythemal UVR levels in passive recreation areas in public parks. UVR levels were measured for point in time comparisons between Solarmeter 6.5 handheld meters and time-stamped electronic dosimeters in a large central park in Melbourne, Australia. Observations were made at 20 locations in the park by two research assistants under two conditions: (1) matched shade (2) contrasting shade-no shade. Comparisons were also made with scientific instruments on the UVR monitoring station rooftop and by remotely selecting UV records and forecasts on cloud-free dates of park observations. There was good agreement between the portable UVR instruments in the park setting as confirmed via Bland Altman plots, while the dosimeter appeared less sensitive to change in shade conditions. The rooftop measurements showed that the Solarmeter 6.5 UVR readings were comparable to those of the adjacent rooftop instruments. The practicalities of using the dosimeters and Solarmeters for behavioral studies are discussed. These findings provide a basis for use of the Solarmeter 6.5 to measure changes in UVR levels due to different environmental conditions with relative accuracy for intervention studies in outdoor settings.

Density of tobacco retail outlets near schools and smoking behaviour among secondary school students.

OBJECTIVE: To investigate whether the density of tobacco retail outlets near schools in Victoria, Australia, is associated with adolescent smoking behaviour. METHODS: Cross-sectional survey data of 2,044 secondary school students aged 12-17 years was combined with tobacco outlet audit data. Associations between students' self-reported tobacco use and the density of tobacco outlets near schools was examined using multilevel logistic and negative binomial regression models, with cigarette price at local milk bars and key socio-demographic and school-related variables included as covariates. RESULTS: Increased tobacco retail outlet density was associated with a significant increase in the number of cigarettes smoked in the previous seven days among students who smoked in the past month (IRR=1.13; 95% CI 1.02-1.26), but not the odds of smoking in the past month in the larger sample (OR=1.06; 95% CI 0.90-1.24), after controlling for local mean price of cigarettes and socio-demographic and school-related variables. CONCLUSIONS AND IMPLICATIONS: This study suggests there is a positive association between tobacco retail outlet density and cigarette consumption among adolescent smokers, but not smoking prevalence, in the Australian context. There is value in considering policy measures that restrict the supply of tobacco retail outlets in school neighbourhoods as a means of reducing youth cigarette consumption.

What impact have tobacco control policies, cigarette price and tobacco control programme funding had on Australian adolescents' smoking? Findings over a 15-year period.

AIMS: To assess the impact of tobacco control policies relating to youth access, clean indoor air and tobacco advertising at point-of-sale and outdoors, in addition to cigarette price and per capita tobacco control spending, on adolescent smoking prevalence. DESIGN: Repeated cross-sectional surveys. Logistic regression analyses examined association between policies and smoking prevalence. SETTING: Australia, 1990-2005. PARTICIPANTS: A nationally representative sample of secondary students (aged 12-17 years) participating in a triennial survey (sample size per survey range: 20 560 to 27 480). MEASUREMENTS: Students' report of past-month smoking. In each jurisdiction, extent of implementation of the three policies for the year of the survey was determined. For each survey year, national per capita tobacco control spending was determined and jurisdiction-specific 12-month change in cigarette price obtained. FINDINGS: Extent of implementation of the three policy areas varied between states and over the survey years. Multivariate analyses that adjusted for demographic factors, year and all tobacco control variables showed that 12-month cigarette price increases [odds ratio (OR): 0.98, 95% confidence interval (CI): 0.97-0.99], greater per capita tobacco control spending (OR: 0.99, 95% CI: 0.98-0.99) and stronger implementation of clean indoor air policies (OR: 0.93, 95% CI: 0.92-0.94) were associated with reduced smoking prevalence. CONCLUSIONS: Adult-directed, population-based tobacco control policies such as clean indoor air laws and increased prices of cigarettes, implemented as part of a well-funded comprehensive tobacco control programme are associated with lower adolescent smoking.

Does the portrayal of tanning in Australian women's magazines relate to real women's tanning beliefs and behavior?

Content analysis data on the tans of 4,422 female Caucasian models sampled from spring and summer magazine issues were combined with readership data to generate indices of potential exposure to social modeling of tanning via popular women's magazines over a 15-year period (1987 to 2002). Associations between these indices and cross-sectional telephone survey data from the same period on 5,675 female teenagers' and adults' tanning attitudes, beliefs, and behavior were examined using logistic regression models. Among young women, greater exposure to tanning in young women's magazines was associated with increased likelihood of endorsing pro-tan attitudes and beliefs. Among women of all ages, greater exposure to tanned models via the most popular women's magazines was associated with increased likelihood of attempting to get a tan but lower likelihood of endorsing pro-tan attitudes. Popular women's magazines may promote and reflect real women's tanning beliefs and behavior.