Isolating the effect of confounding from the observed survival benefit of screening participants - a methodological approach illustrated by data from the German mammography screening programme.

BACKGROUND: Mammography screening programmes (MSP) aim to reduce breast cancer mortality by shifting diagnoses to earlier stages. However, it is difficult to evaluate the effectiveness of current MSP because analyses can only rely on observational data, comparing women who participate in screening with women who do not. These comparisons are subject to several biases: one of the most important is self-selection into the MSP, which introduces confounding and is difficult to control for. Here, we propose an approach to quantify confounding based on breast cancer survival analyses using readily available routine data sources. METHODS: Using data from the Cancer Registry of North Rhine-Westphalia, Germany, we estimate the relative contribution of confounding to the observed survival benefit of participants of the German MSP. This is accomplished by comparing non-participants, participants with screen-detected and participants with interval breast cancers for the endpoints "death from breast cancer" and "death from all causes other than breast cancer" - the latter being assumed to be unrelated to any MSP effect. By using different contrasts, we eliminate the effects of stage shift, lead and length time bias. The association of breast cancer detection mode with survival is analysed using Cox models in 68,230 women, aged 50-69 years, with breast cancer diagnosed in 2006-2014 and followed up until 2018. RESULTS: The hazard of dying from breast cancer was lower in participants with screen-detected cancer than in non-participants (HR = 0.21, 95% CI: 0.20-0.22), but biased by lead and length time bias, and confounding. When comparing participants with interval cancers and non-participants, the survival advantage was considerably smaller (HR = 0.62, 95% CI: 0.58-0.66), due to the elimination of stage shift and lead time bias. Finally, considering only mortality from causes other than breast cancer in the latter comparison, length time bias was minimised, but a survival advantage was still present (HR = 0.63, 95% CI: 0.56-0.70), which we attribute to confounding. CONCLUSIONS: This study shows that, in addition to stage shift, lead and length time bias, confounding is an essential component when comparing the survival of MSP participants and non-participants. We further show that the confounding effect can be quantified without explicit knowledge of potential confounders by using a negative control outcome.

Assessing the probability of risk factor control in patients with coronary heart disease: results from the ESC-EORP EUROASPIRE V survey.

AIMS: In patients with coronary heart disease (CHD), we investigated whether it is possible to accurately assess the probability of short-term control of risk factors (blood pressure, cholesterol, smoking) based on individual and large-area residential characteristics. METHODS AND RESULTS: We merged individual data of participants from EUROASPIRE V who were hospitalized for CHD (2014-2017) and interviewed and examined for risk factor control (2016-2017), with large-area residential data provided by Eurostat for Nomenclature of Territorial Units for Statistics (NUTS) regions using postal codes. Data from 2562 CHD patients in 16 countries were linked to data from 60 NUTS 2 and 121 NUTS 3 regions. The median time between hospitalization and interview was 14 months. We developed prediction models to assess the probability of risk factor control at interview using data from the time of hospitalization: (i) baseline models including 35 variables on patients' demographic, clinical, and socio-economic characteristics and (ii) extended models additionally considering nine variables on large-area residential characteristics. We calculated and internally validated c-indices to assess the discriminative ability of prediction models. Baseline models showed good discrimination with c-indices of 0.69, 0.70, and 0.76 for blood pressure control, cholesterol control, and smoking cessation, respectively. Extended models for blood pressure, cholesterol, and smoking yielded improved c-indices of 0.72, 0.71, and 0.78, respectively. CONCLUSION: Our results indicate that the probability of risk factor control in CHD patients can be accurately assessed using individual and large-area residential characteristics, allowing for an identification of patients who are less likely to achieve risk factor targets.

Secondary analysis of an RCT on Emergency Department-Initiated Tobacco Control: Repeatedly assessed point-prevalence abstinence up to 12 months and extension of results through a 10-year follow-up.

INTRODUCTION: Emergency departments (EDs) are opportune places for tobacco control interventions. The 'Tobacco Control in an Urban Emergency Department' (TED) study, ISRCTN41527831, originally evaluated the effect of motivational interviewing on-site plus up to four booster telephone calls on 12-month abstinence. This study's aim was to evaluate the effect of the intervention on 7-day point-prevalence abstinence at 10 years follow-up (primary outcome) as well as on repeated point-prevalence abstinence at 1, 3, 6, 12 months and at 10 years (continual smoking abstinence, secondary outcome). METHODS: At the 10 years follow-up and after informed consent, study participants responded to a mailed questionnaire. The primary outcome was analyzed in observed-only and in all-cases analyses. The secondary outcomes were analyzed using a multiple adjusted GLMM for binary outcomes. RESULTS: Out of 1012 TED-study participants, 986 (97.4%) were alive and 231 (23.4% of 986) responded to the follow-up at 10 years. For observed-only and all-cases analyses, the effect of the baseline intervention on 7-day point-prevalence abstinence at the 10 years follow-up was statistically non-significant. However, when taking into account all repeated measures, the intervention significantly influenced continual abstinence with odds ratio 1.32 (95% CI: 1.01-1.73; p=0.042). Baseline motivation, perceived self-efficacy to stop smoking, and nicotine dependency were independently associated with long-term continual smoking abstinence (all p<0.05). CONCLUSIONS: A conventional analysis failed to confirm a significant effect of the ED-initiated tobacco control intervention on the point-prevalence abstinence at 10 years. Results from a more integrative analysis nonetheless indicated an enduring intervention effect on continual abstinence among smokers first encountered in the emergency department setting 10 years earlier.

Detection Rates of Ductal Carcinoma in Situ with Biennial Digital Mammography Screening: Radiologic Findings Support Pathologic Model of Tumor Progression.

Purpose To compare detection rates of ductal carcinoma in situ (DCIS), classified according to nuclear grade, between the prevalence round (baseline screening) and two subsequent screening rounds of a population-based digital mammography screening program, to assess differences over time. Materials and Methods The cancer registry provided data for 1970 graded pure DCIS cases from 16 screening regions of the prevalence round (baseline screening, from 2005 to 2008), first subsequent round, and second subsequent round; the interval between all screening rounds was 22-30 months. Age-adjusted logistic regression analysis was performed to compare the grade-specific detection rates between the prevalence round (reference) and subsequent screening rounds. Results Over all screening rounds, cancer detection rates were lowest for low-grade DCIS (range, 0.11 [58 of 508 817 patients] to 0.25 [178 of 713 867 patients] per 1000 women screened) and highest for high-grade DCIS (range, 0.53[271 of 508 817 patients] to 0.59 [237 of 398 944 patients] per 1000 women screened). Detection rates for low-grade DCIS were significantly lower in the first (odds ratio [OR] = 0.45, P < .001) and second (OR = 0.57, P < .001) subsequent screening rounds compared with that in the prevalence round; the relative reduction of detection rates of intermediate-grade DCIS was less pronounced (OR = 0.79, P = .006 and OR = 0.76, P = .003, respectively). Conversely, the detection rate of high-grade DCIS remained at the high level found in the prevalence screening (OR = 0.89, P = .143 and OR = 0.97, P = .700, respectively). Conclusion The findings demonstrate persistently high detection rates of high-grade DCIS in two consecutive subsequent screening rounds compared with the prevalence round; conversely, rates of low-grade DCIS and, less markedly, intermediate-grade DCIS decreased in subsequent rounds. Grade-related changes of DCIS detection are suggestive of distinct dynamics of lesion progression. © RSNA, 2017 An earlier incorrect version of this article appeared online. This article was corrected on November 10, 2017.

Emergency Department-Initiated Tobacco Control: Update of a Systematic Review and Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: A 2012 systematic review and meta-analysis of randomized controlled trials on emergency department-initiated tobacco control (ETC) showed only short-term efficacy. The aim of this study was to update data through May 2015. METHODS: After registering the study protocol on the international prospective register of systematic reviews (PROSPERO) in May 2015, we searched 7 databases and the gray literature. Our outcome of interest was the point prevalence of tobacco-use abstinence at 1-month, 3-month, 6-month, or 12-month follow-up. We calculated the relative risk (RR) of tobacco-use abstinence after ETC at each follow-up time separately for each study and then pooled Mantel-Haenszel RRs by follow-up time. These results were pooled with results of the 7 studies included in the previous review. We calculated the effect of ETC on the combined point prevalence of tobacco-use abstinence across all follow-up times by using generalized linear mixed models. RESULTS: We retrieved 4 additional studies, one published as an abstract, comprising 1,392 participants overall. The 1-month follow-up point prevalence of tobacco-use abstinence after ETC resulted in an RR of 1.49 (95% confidence interval [CI], 1.08-2.05) across 3 studies; 3-month follow-up, an RR of 1.38 (95% CI, 1.12-1.71) across 9 studies; 6-month follow-up, an RR of 1.09 (95% CI, 0.84-1.41) across 6 studies; and 12-month follow-up, an RR of 1.26 (95% CI, 1.00-1.59) across 3 studies. The effect on the combined point prevalence of abstinence was an RR of 1.40 (95% CI, 1.06-1.86) (P = .02). CONCLUSION: ETC is effective in promoting continual tobacco-use abstinence up to 12 months after intervention. ETC may be a critically important public health strategy for engaging hard-to-reach smokers in tobacco-use cessation.

Impact of major depressive disorder, distinct subtypes, and symptom severity on lifestyle in the BiDirect Study.

The aim of this study was to examine associations of major depressive disorder (MDD), its distinct subtypes, and symptom severity with the individual lifestyle factors smoking, diet quality, physical activity, and body mass index as well as with a combined lifestyle index measuring the co-occurrence of these lifestyle factors. A sample of 823 patients with MDD and 597 non-depressed controls was examined. The psychiatric assessment was based on a clinical interview including the Mini International Neuropsychiatric Interview and the Hamilton Depression Rating Scale. Each lifestyle factor was scored as either healthy or unhealthy, and the number of unhealthy lifestyle factors was added up in a combined lifestyle index. Cross-sectional analyses were performed using alternating logistic regression and ordinal logistic regression, adjusted for socio-demographic characteristics. After adjustment, MDD was significantly associated with smoking, low physical activity, and overweight. Likewise, MDD was significantly related to the overall lifestyle index. When stratifying for subtypes, all subtypes showed higher odds for an overall unhealthier lifestyle than controls, but the associations with the individual lifestyle factors were partly different. Symptom severity was associated with the lifestyle index in a dose-response manner. In conclusion, patients with MDD represent an important target group for lifestyle interventions.

Association between major depressive disorder and odor identification impairment.

BACKGROUND: There is evidence of olfactory deficits in patients with major depressive disorder (MDD) but causes and mechanisms are largely unknown. METHODS: We compared 728 patients with current MDD and 555 non-depressed controls regarding odor identification impairment taking into account the severity of acute symptoms and of the disease course. We assessed current symptom severity with the Hamilton Depression Rating Scale, and disease course severity based on admission diagnosis (ICD-10, F32/F33) and self-reported hospitalization frequency, defined as infrequent (<2) and frequent (≥2) depression-related hospitalizations under constant disease duration. A score of <10 on the Sniffin' Sticks-Screen-12 test determined the presence of odor identification impairment. RESULTS: Compared to non-depressed controls patients with frequent (rapidly recurring) hospitalizations had an elevated chance of odor identification impairment, even after adjustment for smell-influencing factors, such as age and smoking, (OR=1.7; 95% CI 1.0-2.9). Patients with recurrent MDD (F33) also had an elevated odds of odor identification impairment compared to those with a first-time episode (F32, OR=1.5; 95% CI 1.0-2.4). In patients with a first-time episode the chance of odor identification impairment increased by 7% with each point increase in the Hamilton Score. LIMITATIONS: Cross-sectional study. Variation in the use of psychotropic medication is a potential bias. CONCLUSION: Odor identification impairment was evident in MDD patients with first-time high symptom severity and in patients with a severe disease course. Whether odor identification impairment is a marker or mediator of structural and functional brain changes associated with acute or active MDD requires further investigations in longitudinal studies.

Determinants of Single and Multiple Sensory Impairments in an Urban Population.

OBJECTIVE: To describe the co-occurrence pattern and determinants of auditory, olfactory, visual, and gustatory impairment across the life spectrum of adults. STUDY DESIGN: Cross-sectional analysis. SETTING: An urban population. SUBJECTS AND METHOD: In total, 1208 persons from the general adult population (age range, 25-74 years; 46.7% men) were included. Sensory impairments were assessed with validated tests. Alternating logistic regression was applied to characterize (1) the dependence of sensory impairments on selected independent variables and (2) the pairwise association between sensory impairments. The dependence of impairment grade (no to multisensory impairment) on the same set of independent variables was examined using ordinal logistic regression. RESULTS: The prevalence of single sensory impairment was 38.8%, of dual 27.3%, and of multisensory impairment 7.5%. Auditory impairment was the most frequent impairment type (43.9%), followed by olfactory (21.5%), gustatory (20.3%), and visual impairment (14.1%). Besides age and sex, social status (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.80-3.79), smoking status (OR, 1.45; 95% CI, 1.12-1.88), and diabetes (OR, 1.75; 95% CI, 1.16-2.63) were related to an elevated odds of moving from a lower into a higher impairment category. CONCLUSIONS: The presence of certain risk factors, such as a low social status, diabetes, and smoking, appears likely to increase the risk of multisensory impairment.

Readiness for smoking cessation in coronary heart disease patients across Europe: Results from the EUROASPIRE III survey.

BACKGROUND: Readiness for smoking cessation is an important predictor of quit attempts and cessation success. We aimed to investigate the prevalence and correlates of readiness for smoking cessation in coronary heart disease (CHD) patients. DESIGN: The EUROpean Action on Secondary and Primary Prevention by Intervention to Reduce Events III (EUROASPIRE III) survey is a cross-sectional study conducted in 2006-2007 among CHD patients <80 years of age from 22 European regions. METHODS: Patients were interviewed on average 15 months after hospital admission for an acute coronary event or procedure. Readiness for smoking cessation was assessed using the smoking stages of change (SSC) short form questionnaire. Breath carbon monoxide was measured to validate self-reported non-smoking. RESULTS: Among 2585 patients who were smoking prior to hospital admission, 25.6%, 16.8%, 8.1%, 5.6% and 44.0% were in the precontemplation (no intention to quit), contemplation (thinking of quitting), preparation (planning to quit), action (having quit within six months) and maintenance (having quit more than six months ago) stages, respectively. Significant multivariable correlates of advancement in SSC showed positive associations of older age and attended cardiac rehabilitation and negative associations of severe depressive symptoms, longer smoking duration and environmental tobacco smoke (ETS) exposure. CONCLUSIONS: One-quarter of CHD patients across Europe who were smoking prior to hospitalisation have no intention to quit, and an additional quarter is thinking of quitting or planning to quit. Patients who are younger, do not attend cardiac rehabilitation, have severe depressive symptoms, have been smoking for longer periods of time and are exposed to ETS may need to be specifically targeted in cessation interventions.

Passive smoking and smoking cessation among patients with coronary heart disease across Europe: results from the EUROASPIRE III survey.

AIMS: Passive smoking is the inhalation of environmental tobacco smoke (ETS) and is a risk factor for coronary heart disease (CHD). We aimed to describe the frequency of passive smoking among patients with CHD and to investigate the association between ETS exposure and smoking cessation. METHODS AND RESULTS: The EUROASPIRE III survey was conducted in 2006-07 among CHD patients up to 80 years of age from 22 European regions. Patients were interviewed and examined on average 15 months after hospital admission for CHD. Information was obtained on smoking prior to hospital admission, smoking at interview, and ETS exposure at home, at work, and at other locations. Breath carbon monoxide was measured to validate self-reported non-smoking. Among 8729 patients, 6060 (69.4%) were non-smokers prior to hospital admission, of whom 10.3% reported ETS exposure at home, 7.2% at work, and 13.8% at other locations. Overall, 24.2% of non-smokers were exposed to ETS at any place. Among the 2669 patients who were smoking prior to hospital admission, the likelihood of cessation at interview was lower in those with ETS exposure at home than in those without [25.3 vs. 58.1%; adjusted odds ratio (OR) 0.26, 95% confidence interval (CI) 0.20-0.33]. This finding applied also to ETS exposure at work (32.2 vs. 52.7%; adjusted OR 0.56, 95% CI 0.42-0.76) and at other locations (38.0 vs. 52.8%; adjusted OR 0.63, 95% CI 0.48-0.84). CONCLUSION: A noteworthy proportion of non-smokers with CHD are exposed to ETS. Passive smoking may jeopardize smoking cessation among CHD patients.

Efficacy of emergency department-initiated tobacco control--systematic review and meta-analysis of randomized controlled trials.

AIM: Systematic review and meta-analysis of randomized controlled trials evaluating the efficacy of emergency department-initiated tobacco control (ETC). METHODS: Literature search in 7 databases and gray literature sources. Point prevalence tobacco abstinence at 1-, 3-, 6-, and/or 12-month follow-up was abstracted from each study. The proportionate effect (relative risk) of ETC on tobacco abstinence was calculated separately for each study and follow-up time and pooled, at different follow-up times, by Mantel-Haenszel relative risks. The effects of ETC on combined point prevalence tobacco abstinence across all follow-up times were calculated using generalized linear mixed models. RESULTS: Seven studies with overall 1,986 participants were included. The strongest effect of ETC on point prevalence tobacco abstinence was found at 1 month: Relative risk (RR) = 1.47 (3 studies) (95% confidence interval [CI]: 1.06-2.06), while the effect at 3, 6, and 12 months was RR = 1.24 (6 studies) (95% CI: 0.93-1.65); 1.13 (5 studies) (95% CI: 0.86-1.49); and 1.25 (1 study) (95% CI: 0.91-1.72). The benefit on combined point prevalence tobacco abstinence was RR = 1.33 (7 studies) (95% CI: 0.96-1.83), p = .08; with RR = 1.33 (95% CI: 0.92-1.92), p = .10, for the 5 studies combining motivational interviewing and booster phone calls. CONCLUSIONS: ETC combining motivational interviewing and booster phone calls showed a trend toward increased episodically measured tobacco abstinence up to 12 months. More methodologically rigorous trials are needed to effectively evaluate the impact of ETC.

Trends in cardiovascular risk factors among patients with coronary heart disease: results from the EUROASPIRE I, II, and III surveys in the Münster region.

BACKGROUND: Target values for cardiovascular risk factors in patients with coronary heart disease (CHD) are stated in guidelines for the prevention of cardiovascular disease. We studied secular trends in risk factors over a 12-year period among CHD patients in the region of Münster, Germany. METHODS: The cross-sectional EUROASPIRE I, II and III surveys were performed in multiple centers across Europe. For all three, the Münster region was the participating German region. In the three periods 1995/96, 1999/2000, and 2006/07, the surveys included (respectively) 392, 402 and 457 ≤ 70-year-old patients with CHD in Münster who had sustained a coronary event at least 6 months earlier. RESULTS: The prevalence of smoking remained unchanged, with 16.8% in EUROASPIRE I and II and 18.4% in EUROASPIRE III (p=0.898). On the other hand, high blood pressure and high cholesterol both became less common across the three EUROASPIRE studies (60.7% to 69.4% to 55.3%, and 94.3% to 83.4% to 48.1%, respectively; p<0.001 for both). Obesity became more common (23.0% to 30.6% to 43.1%, p<0.001), as did treatment with antihypertensive and lipid-lowering drugs (80.4% to 88.6% to 94.3%, and 35.0% to 67.4% to 87.0%, respectively; p<0.001 for both). CONCLUSION: The observed trends in cardiovascular risk factors under-score the vital need for better preventive strategies in patients with CHD.

Cancer incidence in type 2 diabetes patients - first results from a feasibility study of the D2C cohort.

BACKGROUND: A large prospective study in patients with type 2 diabetes (T2D), the German D2C cohort, is presently being enumerated to investigate risk factors of incident cancer in diabetic patients. STUDY SETTING: A disease management program was offered, on a voluntary basis, to all T2D patients who were members of a statutory health insurance fund in Germany. This first feasibility report uses data from 26.742 T2D patients, who were 40 to 79 years old, resided in the Muenster District, and who were enrolled between June 2003 and July 2008. Cancer cases were identified through the regional Cancer Registry. METHODS: Invasive cancer cases were identified using probabilistic record linkage procedures and pseudonymised personal identifiers. Censoring date was December 31, 2008. We included only first cancers, leaving 12.650 male and 14.092 female T2D with a total of 88.778 person-years (py). We computed standardised incidence ratios (SIR) for external comparisons and we employed Cox regression models and hazard ratios (HR) within the cohort. RESULTS: We identified 759 first cancers among male T2D patients (18.7 per 1,000 py) and 605 among females (12.7 per 1,000 py). The risk of any incident cancer in T2D was raised (SIR = 1.14; 95% confidence interval [1.10 - 1.21]), in particular for cancer of the liver (SIR = 1.94 [1.15 - 2.94]) and pancreas (SIR = 1.45 [1.07-1.92]). SIRs decreased markedly with time after T2D diagnosis. In Cox models, adjusting for diabetes duration, body mass index and sex, insulin therapy was related to higher cancer risk (HR = 1.25 [1.17 - 1.33]). No effect was seen for metformin. DISCUSSION: Our study demonstrates feasibility of record linkage between DMP and cancer registries. These first cohort results confirm previous reports. It is envisaged to enhance this cohort by inclusion of further regions of the state, expansion of the follow-up times, and collection of a more detailed medication history.

The efficacy of erythropoietin and its analogues in animal stroke models: a meta-analysis.

BACKGROUND AND PURPOSE: Erythropoietin (EPO) was explored regarding its suitability as a candidate stroke drug in animal experimental studies. We performed a meta-analysis to obtain an overall impression of the efficacy of EPO in published animal experimental stroke studies and for potential guidance of future clinical studies. METHODS: By electronic and manual searches of the literature, we identified studies describing the efficacy of EPO in experimental focal cerebral ischemia. Data on study quality, EPO dose, time of administration, and outcome measured as infarct volume or functional deficit were extracted. Data from all studies were pooled by means of a meta-analysis. RESULTS: Sixteen studies were included in the meta-analysis. When administered after the onset of ischemia, EPO and its analogues reduced infarct size by 32% and improved neurobehavioral deficits significantly. A meta-regression suggests higher doses of EPO to be associated with smaller infarct volumes. When administered earlier than 6 hours EPO was more effective compared to a later treatment initiation. Both hematopoietic and nonhematopoietic EPO analogues showed efficacy in experimental stroke. CONCLUSIONS: In conclusion, this analysis further strengthens confidence in the efficacy of EPO and its analogues in stroke therapy. Nonhematopoietic EPO analogues which are known to have less systemic adverse effects compared to EPO are also promising candidate stroke drugs. Further experimental studies are required that evaluate the safety of a combination of EPO with thrombolysis and whether EPO is also effective in animals with comorbidity.

Cardiovascular risk factors and mortality in patients with coronary heart disease.

A priority in preventive cardiology is to reduce the number of recurrent events and to prolong survival in patients with established coronary heart disease (CHD). Aim of the present study was to examine risk factors for long-term mortality in CHD patients who entered routine secondary prevention after a coronary event or intervention. Such patients, from the EUROASPIRE (EUROpean Action on Secondary Prevention through Intervention to Reduce Events) I and II studies in the region of Münster, Germany, were followed over a mean period of 8.0 years up to the end of 2005. Patients were up to 70 years of age at baseline when they were interviewed and examined using standardised methods. Baseline examination was carried out at least 6 months and at a mean of 19.5 months after the coronary event or procedure. In 367 patients from EUROASPIRE I and 380 patients from EUROASPIRE II, a total of 125 deaths (16.7%) occurred during follow-up. Multivariate analyses, using Cox proportional hazards models, established diabetes mellitus and smoking as predictors for all-cause mortality with estimated hazard rate ratios (HRRs) of 2.24 (95% confidence interval (CI): 1.43-3.49) and 1.95 (95% CI: 1.23-3.10), respectively. Significant associations were found between diabetes mellitus and cardiovascular (HRR 2.36; 95% CI: 1.31-4.24) as well as CHD mortality (HRR 2.40; 95% CI: 1.25-4.59). Systolic blood pressure was significantly associated with increased cerebrovascular disease mortality (HRR 1.04; 95% CI: 1.01 and 1.08 for 1 mmHg increase). In conclusion, long-term mortality in coronary patients from routine secondary prevention is substantial. Diabetes mellitus and smoking represent key issues in patients with established CHD.

Meta-analysis of the efficacy of granulocyte-colony stimulating factor in animal models of focal cerebral ischemia.

BACKGROUND AND PURPOSE: Recent reports have described the efficacy of the hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) in animal stroke models. Early clinical multicenter trials evaluating the effect of G-CSF in acute stroke and pilot clinical trials for the subacute phase are ongoing. To guide further development, a meta-analysis was performed to assess the effects of G-CSF on infarct size and sensorimotor deficits. METHODS: Using electronic and manual searches of the literature, we identified studies describing the efficacy of G-CSF in animal models of focal cerebral ischemia. Two reviewers independently selected studies and extracted data on study quality, G-CSF doses, time of administration, and outcome measured as infarct volume and/or sensorimotor deficit. Data from all studies were pooled by meta-regression analyses. RESULTS: Thirteen studies including 277 animals for infarct size calculation and 258 animals for assessment of sensorimotor deficit met the criteria for inclusion. Overall efficacy of G-CSF regarding infarct size reduction was 42%. Meta-regression analysis revealed a 0.8% (P<0.0001) decrease in infarct size per 1-mug/kg increase in G-CSF dose when applied within the first 6 hours and a 2.1% (P<0.0001) decrease when applied later than 6 hours after induction of ischemia with a significant (P=0.0004) greater infarct size reduction after delayed treatment. Sensorimotor deficits categorized into 3 subgroups improved between 24% and 40%. CONCLUSIONS: Our findings consolidate G-CSF as a drug that both reduces infarct size and enhances functional recovery. These effects are presumably dose dependent. In contrast to most other neuroprotectants, a beneficial outcome may also be achieved when treatment is delayed.

Stroke mortality and morbidity attributable to passive smoking in Germany.

BACKGROUND: Passive smoking is an established risk factor for coronary heart disease (CHD). Epidemiological studies suggest that passive smoking may also be associated with an increased risk of stroke. We estimate the burden of stroke due to passive smoking in Germany. METHODS: Frequency of passive smoking was derived from the German national health survey. Nonsmokers who reported exposure to environmental tobacco smoke (ETS) at home were considered for analyses. The relative risk for stroke and passive smoking was derived by means of a meta-analysis from available cohort studies. We computed attributable risks for passive smoking and used data from official statistics to estimate stroke mortality due to ETS. Attributable stroke morbidity was calculated using the WHO-Global-Burden-of-Disease approach. RESULTS: Passive smoking may account for 774 stroke-related deaths and 1837 incident first ever strokes in Germany every year. More strokes owing to passive smoking occur among women (1248) than among men (589). The majority of strokes attributable to ETS happen at the age of 65-84 years. CONCLUSION: ETS is a common exposure and stroke is a frequent disease. Though the relative risk of passive smoking on stroke mortality and morbidity is small, the impact on population health is substantial.

Mortality and morbidity from coronary heart disease attributable to passive smoking.

AIMS: Passive smoking is associated with increased risk of coronary heart disease (CHD). This study estimates CHD mortality and morbidity attributable to passive smoking in Germany and demonstrates variations in the number of estimated deaths depending on underlying assumptions. METHODS AND RESULTS: Prevalence of passive smoking from the German National Health Survey, CHD deaths from national mortality statistics, number of incident CHD cases, and relative risks from meta-analyses were used to estimate mortality and morbidity from passive smoking applying the concept of population attributable risk. Sensitivity analyses were carried out to investigate the impact of different assumptions in terms of exposure definition, relative risk, and population at risk on estimated mortality. Exposure to environmental tobacco smoke (ETS) at home accounts for 2148 [approximate 95% confidence interval (CI) 1471-2736] deaths from CHD and 3776 (95% CI 2588-4800) incident CHD cases among non-smokers every year in Germany. In sensitivity analyses, consideration of exposure to ETS at work and at any location yielded 2597 (95% CI 1784-3295) and 8970 (95% CI 6252-11 243) attributable CHD deaths, respectively. Applying different populations at risk showed a range of 1174 (95% CI 803-1494) to 13 792 (95% CI 9655-17 225) attributable deaths from CHD. CONCLUSION: The estimated burden of passive smoking heavily depends on the definition of underlying parameters. Using an evidence-based approach reveals a substantial burden of passive smoking in terms of CHD mortality and morbidity reflected by six CHD deaths and 10 incident CHD cases every day in Germany.

Lung cancer mortality and carbon black exposure: Cox regression analysis of a cohort from a German carbon black production plant.

OBJECTIVE: We undertook a lung cancer mortality analysis of 1528 German carbon black workers, followed between the years of 1976-1998, who produced furnace black, lamp black, and gas black. METHODS: We used Cox modeling across age with time-dependent covariates, ie, cumulative and mean carbon black exposure, duration of work in departments, adjusting for calendar time, a smoking indicator, and age at hire. Exposures were lagged up to 20 years. Analyses were performed with the full cohort and after restriction to an inception cohort. RESULTS: A total of 50 lung cancer deaths occurred. No positive association was found with carbon black exposure indices. Some models indicated an increasing risk across duration of work in the lamp black producing department. CONCLUSIONS: Our results do not suggest that carbon black exposure is a human lung carcinogen. The lamp black results, if no artifact, may point at historical exposures to gaseous polycyclic aromatic hydrocarbons.

Lung cancer mortality and carbon black exposure: a nested case-control study at a German carbon black production plant.

OBJECTIVE: The objective of this study was to conduct a case-control study of lung cancer nested within a cohort of 1528 German carbon black workers, 1976-1998. METHODS: The authors conducted risk-set sampling of two controls matched on year of birth and conditional logistic regression modeling of cumulative carbon black exposure, duration of work in different departments, feedstock contact, asbestos exposure, smoking, age at hire, exposures before the carbon black job, and serving as a soldier in World War II or being a prisoner of war. Analyses were performed with both the full cohort and members of an inception cohort subset. Exposures were lagged by 10 years. RESULTS: Analysis of 50 lung cancer deaths showed no association to carbon black exposure. CONCLUSIONS: Carbon black exposure was not linked to lung cancer risk. Suggestions of positive associations with asbestos exposure, feedstock contact, and work in specific departments are inconclusive due to small numbers.