Gender differences in lung cancer epidemiology - do Austrian male lung cancer patients still die earlier in life?

Objective: Previous analyses reported an unexpected decline of mean age of death of Austrian male lung cancer patients until 1996 and a subsequent turnaround of this epidemiological trend after the mid-1990s until 2007. In light of ongoing changes in smoking behavior of men and women, this study aims to investigate the development of mean age of death from lung cancer in Austria during the past three decades. Materials and methods: This study used data about the annual mean age of death from lung cancer, including malignant neoplasm of trachea, bronchus and lung, between 1992 and 2021 obtained from Statistics Austria, Federal Institution under Public Law. One-way analysis of variance (ANOVA) and independent samples t-tests were applied to explore any significant differences of mean values in the course of time as well as between men and women. Results: Overall, mean age of death of male lung cancer patients increased consistently throughout the observed time periods, whereas women did not show any statistically significant change in the last decades. Conclusion: Possible reasons for the reported epidemiological development are discussed in this article. Research and Public Health measures should increasingly focus on smoking behaviors of female adolescents.

Price Policy and Taxation as Effective Strategies for Tobacco Control.

Objective: Only 13% of the world's population are living in countries imposing appropriate tobacco tax-rates. This study aims to promote the implementation of price policy measures as a striking tobacco control strategy in Austria and to encourage other countries to further increase their taxes to WHO best-practice levels. Method: This study used the yearly economic data from Austria from 1997 to 2015. Applying a model for regression analysis, the price elasticity of total tobacco consumption was estimated. Results: Between 1997 and 2015 the price elasticity of demand for tobacco products (including cigarettes, cigars, and other tobaccos) was -0.661, however, the result is statistically insignificant. When excluding 2 anomalous years and removing a variable of the regression model the elasticity was -0.691 and statistically significant, indicating that a 1% increase in tobacco prices will result in a 0.691% decrease of tobacco consumption. Conclusion: The responsiveness of Austrian smokers to price changes has increased during the last decades. Because other activities showed no significance in the analysis, this study should encourage countries world-wide to use price policy and taxation more intensively in order to reduce smoking rates effectively.

Highly aminated iron oxide nanoworms for simultaneous manufacturing and labeling of chimeric antigen receptor T cells.

Cell based therapies including chimeric antigen receptor (CAR) T cells are promising for treating leukemias and solid cancers. At the same time, there is interest in enhancing the functionality of these cells via surface decoration with nanoparticles (backpacking). Magnetic nanoparticle cell labeling is of particular interest due to opportunities for magnetic separation, in vivo manipulation, drug delivery and magnetic resonance imaging (MRI). While modification of T cells with magnetic nanoparticles (MNPs) was explored before, we questioned whether MNPs are compatible with CAR-T cells when introduced during the manufacturing process. We chose highly aminated 120 nm crosslinked iron oxide nanoworms (CLIO NWs, ~36,000 amines per NW) that could efficiently label different adherent cell lines and we used CD123 CAR-T cells as the labeling model. The CD123 CAR-T cells were produced in the presence of CLIO NWs, CLIO NWs plus protamine sulfate (PS), or PS only. The transduction efficiency of lentiviral CD123 CAR with only NWs was ~23% lower than NW+PS and PS groups (~33% and 35%, respectively). The cell viability from these three transduction conditions was not reduced within CAR-T cell groups, though lower compared to non-transduced T cells (mock T). Use of CLIO NWs instead of, or together with cationic protamine sulfate for enhancement of lentiviral transduction resulted in comparable levels of CAR expression and viability but decreased the proportion of CD8+ cells and increased the proportion of CD4+ cells. CD123 CAR-T transduced in the presence of CLIO NWs, CLIO NWs plus PS, or PS only, showed similar level of cytotoxicity against leukemic cell lines. Furthermore, fluorescence microscopy imaging demonstrated that CD123 CAR-T cells labeled with CLIO NW formed rosettes with CD123+ leukemic cells as the non-labeled CAR-T cells, indicating that the CAR-T targeting to tumor cells has maintained after CLIO NW labeling. The in vivo trafficking of the NW labeled CAR-T cells showed the accumulation of CAR-T labeled with NWs primarily in the bone marrow and spleen. CAR-T cells can be magnetically labeled during their production while maintaining functionality using the positively charged iron oxide NWs, which enable the in vivo biodistribution and tracking of CAR-T cells.

Complement opsonization of nanoparticles: Differences between humans and preclinical species.

The complement system plays a key role in opsonization and immune clearance of engineered nanoparticles. Understanding the efficiency, inter-subject, and inter-strain differences of complement opsonization in preclinical species can help with translational nanomedicine development and improve our ability to model complement response in humans. Dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles and a wide range of non-magnetic iron oxide nanoparticle formulations are widely used in magnetic resonance imaging and as clinically approved iron supplements. Previously we found that opsonization of SPIO nanoworms (NW) with the third complement protein (C3) proceeds mostly via the alternative pathway in humans, and via the lectin pathway in mice. Here, we studied the pathway and efficiency of opsonization of 106 nm SPIO NW with C3 in different preclinical species and commonly used laboratory strains. In sera of healthy human donors (n = 6), C3 opsonization proceeded exclusively through the alternative pathway. On the other hand, the C3 opsonization in dogs (6 breeds), rats (4 strains) and mice (5 strains) sera was either partially or completely dependent on the complement Ca2+-sensitive pathways (lectin and/or classical). Specifically, C3 opsonization in sera of Long Evans rat strain, and mouse strains widely used in nanomedicine research (BALB/c, C57BL/6 J, and A/J) was only through the Ca2+-dependent pathways. Dogs and humans had the highest between-subject variability in C3 opsonization levels, while rat and mouse sera showed the lowest between-strain variability. Furthermore, using a panel of SPIO nanoparticles of different sizes and dextran coatings, we found that the level of C3 opsonization (C3 molecules per milligram Fe) in human sera was lower than in animal sera. At the same time, there was a strong predictive value of complement opsonization in dog and rat sera; nanoparticles with higher C3 deposition in animals showed higher deposition in humans, and vice versa. Notably, the opsonization decreased with decreasing size in all sera. The studies highlight the importance of the consideration of species and strains for predicting human complement responses (opsonization) towards nanomedicines.

Complement Inhibitors Block Complement C3 Opsonization and Improve Targeting Selectivity of Nanoparticles in Blood.

Complement is one of the critical branches of innate immunity that determines the recognition of engineered nanoparticles by immune cells. Antibody-targeted iron oxide nanoparticles are a popular platform for magnetic separations, in vitro diagnostics, and molecular imaging. We used 60 nm cross-linked iron oxide nanoworms (CLIO NWs) modified with antibodies against Her2/neu and EpCAM, which are common markers of blood-borne cancer cells, to understand the role of complement in the selectivity of targeting of tumor cells in whole blood. CLIO NWs showed highly efficient targeting and magnetic isolation of tumor cells spiked in lepirudin-anticoagulated blood, but specificity was low due to high uptake by neutrophils, monocytes, and lymphocytes. Complement C3 opsonization in plasma was predominantly via the alternative pathway regardless of the presence of antibody, PEG, or fluorescent tag, but was higher for antibody-conjugated CLIO NWs. Addition of various soluble inhibitors of complement convertase (compstatin, soluble CD35, and soluble CD55) to whole human blood blocked up to 99% of the uptake of targeted CLIO NWs by leukocytes, which resulted in a more selective magnetic isolation of tumor cells. Using well-characterized nanomaterials, we demonstrate here that complement therapeutics can be used to improve targeting selectivity.

Feraheme (Ferumoxytol) Is Recognized by Proinflammatory and Anti-inflammatory Macrophages via Scavenger Receptor Type AI/II.

Feraheme (ferumoxytol), a negatively charged, carboxymethyl dextran-coated ultrasmall superparamagnetic iron oxide nanoparticle (USPIO, 30 nm, -16 mV), is clinically approved as an iron supplement and is used off-label for magnetic resonance imaging (MRI) of macrophage-rich lesions, but the mechanism of recognition is not known. We investigated mechanisms of uptake of Feraheme by various types of macrophages in vitro and in vivo. The uptake by mouse peritoneal macrophages was not inhibited in complement-deficient serum. In contrast, the uptake of larger and less charged SPIO nanoworms (60 nm, -5 mV; 120 nm, -5 mV, respectively) was completely inhibited in complement deficient serum, which could be attributed to more C3 molecules bound per nanoparticle than Feraheme. The uptake of Feraheme in vitro was blocked by scavenger receptor (SR) inhibitor polyinosinic acid (PIA) and by antibody against scavenger receptor type A I/II (SR-AI/II). Antibodies against other SRs including MARCO, CD14, SR-BI, and CD11b had no effect on Feraheme uptake. Intraperitoneally administered PIA inhibited the peritoneal macrophage uptake of Feraheme in vivo. Nonmacrophage cells transfected with SR-AI plasmid efficiently internalized Feraheme but not noncharged ultrasmall SPIO of the same size (26 nm, -6 mV), suggesting that the anionic carboxymethyl groups of Feraheme are responsible for the SR-AI recognition. The uptake by nondifferentiated bone marrow derived macrophages (BMDM) and by BMDM differentiated into M1 (proinflammatory) and M2 (anti-inflammatory) types was efficiently inhibited by PIA and anti-SR-AI/II antibody. Interestingly, all BMDM types expressed similar levels of SR-AI/II. In conclusion, Feraheme is efficiently recognized via SR-AI/II but not via complement by different macrophage types. The recognition by the common phagocytic receptor has implications for specificity of imaging of macrophage subtypes.

Influenza vaccination in Austria: Persistent resistance and ignorance to influenza prevention and control.

OBJECTIVE: In the Austrian population approximately 350,000-400,000 cases and 1,000-1,200 deaths are observed during an average epidemic, which puts influenza-related deaths on top of the list of vaccine-preventable cases of death. In face of extensive vaccination recommendations, the current vaccination rate of the general population of about 6% is one of the lowest worldwide. The objective of this study was to provide an update regarding the use of influenza vaccination in Austria over the period 1982-2015. METHODS: This paper presents data on influenza vaccine use in Austria displayed by the number of distributed doses per 1,000 population over a period of 33 years. Further data was collected from representative population-based telephone surveys. RESULTS: Austria has always been among the countries with a low number of distributed doses of influenza vaccine. The highest number ever was reached in 2006 with 142 doses/1,000. From 2007 onwards, a steady decrease happened to 62 doses/1,000 in the 2015/16 season, which corresponds to the level of the mid-nineties. CONCLUSION: Despite the fact that Austria is a country with comprehensive recommendations for influenza vaccination, this vaccination continues to be misjudged by the Austrian population and many areas of the medical system. From a public health point of view, this situation is not acceptable. Efforts must be increased to attain a much higher vaccination rate, e.g. the importance of the healthcare workers' influence must be recognized, the options of social marketing have to be utilized and studies on the main barriers in Austria are urgently needed.

Complement therapeutics meets nanomedicine: overcoming human complement activation and leukocyte uptake of nanomedicines with soluble domains of CD55.

Complement activation plays an important role in pharmacokinetic and performance of intravenously administered nanomedicines. Significant efforts have been directed toward engineering of nanosurfaces with low complement activation, but due to promiscuity of complement factors and redundancy of pathways, it is still a major challenge. Cell membrane-anchored Decay Accelerating Factor (DAF, a.k.a. CD55) is an efficient membrane bound complement regulator that inhibits both classical and alternative C3 convertases by accelerating their spontaneous decay. Here we tested the effect of various short consensus repeats (SCRs, "sushi" domains) of human CD55 on nanoparticle-mediated complement activation in human sera and plasma. Structural modeling suggested that SCR-2, SCR-3 and SCR-4 are critical for binding to the alternative pathway C3bBb convertase, whereas SCR-1 is dispensable. Various domains were expressed in E.coli and purified by an affinity column. SCRs were added to lepirudin plasma or sera from different healthy subjects, to monitor nanoparticle-mediated complement activation as well as C3 opsonization. Using superparamagnetic iron oxide nanoworms (SPIO NWs), we found that SCR-2-3-4 was the most effective inhibitor (IC50 ~0.24 µM for C3 opsonization in sera), followed by SCR-1-2-3-4 (IC50 ~0.6 µM), whereas shorter domains (SCR-3, SCR-2-3, SCR-3-4) were ineffective. SCR-2-3-4 also inhibited C5a generation (IC50 ~0.16 µM in sera). In addition to SPIO NWs, SCR-2-3-4 effectively inhibited C3 opsonisation and C5a production by clinically approved nanoparticles (Feraheme, LipoDox and Onivyde). SCR-2-3-4 inhibited both lectin and alternative pathway activation by nanoparticles. When added to lepirudin-anticoagulated blood from healthy donors, it significantly reduced the uptake of SPIO NWs by neutrophils and monocytes. These results suggest that soluble domains of membrane-bound complement inhibitors are potential candidates for preventing nanomedicine-mediated complement activation in human subjects.

Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles.

Deposition of complement factors (opsonization) on nanoparticles may promote clearance from the blood by macrophages and trigger proinflammatory responses, but the mechanisms regulating the efficiency of complement activation are poorly understood. We previously demonstrated that opsonization of superparamagnetic iron oxide (SPIO) nanoworms with the third complement protein (C3) was dependent on the biomolecule corona of the nanoparticles. Here we show that natural antibodies play a critical role in C3 opsonization of SPIO nanoworms and a range of clinically approved nanopharmaceuticals. The dependency of C3 opsonization on immunoglobulin binding is almost universal and is observed regardless of the complement activation pathway. Only a few surface-bound immunoglobulin molecules are needed to trigger complement activation and opsonization. Although the total amount of plasma proteins adsorbed on nanoparticles does not determine C3 deposition efficiency, the biomolecule corona per se enhances immunoglobulin binding to all nanoparticle types. We therefore show that natural antibodies represent a link between biomolecule corona and C3 opsonization, and may determine individual complement responses to nanomedicines.

Publisher Correction: Immunoglobulin deposition on biomolecule corona determines complement opsonization efficiency of preclinical and clinical nanoparticles.

In the version of this Article originally published, a technical error led to Fig. 1a containing '!!!!!!!!' above the scale bar. This has now been corrected in all versions of the Article.

[Immunizing is not only a children's matter! : Why vaccinations are also important for adults]. / Impfen ist nicht nur Kindersache! : Warum Impfungen auch für Erwachsene wichtig sind.

Vaccinations belong to the ten most effective public health achievements worldwide. While immunization programms for children are installed in Europe, vaccinations for adults are not established. However, adult vaccination is extremely meaningful: increasing age means a higher susceptibility to infectious diseases, health problems and multimorbidity will increase. The burden of vaccine-preventable diseases is still high in Europe. Due to immunosenescence (older) adults are less protected against pathogens, antibody titers after vaccinations are lower and immunity lasts shorter. There is striking lack of data of adult vaccination rates and an international consensus regarding adult vaccination recommendations or guidelines are not available in Europe. In only six countries a comprehensive document describing recommended vaccinations for adults is available, among them Austria. The awareness of the importance of adult vaccination over the whole lifetime is not present to the necessary extent in Europe and has to be promoted.

Accelerated Blood Clearance of Antibodies by Nanosized Click Antidotes.

Long blood half-life is one of the advantages of antibodies over small molecule drugs. At the same time, prolonged half-life is a problem for imaging applications or in the case of antibody-induced toxicities. There is a substantial need for antidotes that can quickly clear antibodies from systemic circulation and peripheral tissues. Engineered nanoparticles exhibit intrinsic affinity for clearance organs (mainly liver and spleen). trans-Cyclooctene (TCO) and methyltetrazine (MTZ) are versatile copper-free click chemistry components that are extensively being used for in vivo bioorthogonal couplings. To test the ability of nanoparticles to eliminate antibodies, we prepared a set of click-modified, clinically relevant antidotes based on several classes of drug carriers: phospholipid-PEG micelles, bovine serum albumin (BSA), and cross-linked dextran iron oxide (CLIO) nanoparticles. Mice were injected with IRDye 800CW-labeled, click-modified IgG followed by a click-modified antidote or PBS (control), and the levels of the IgG were monitored up to 72 h postinjection. Long-circulating lipid micelles produced a spike in IgG levels at 1 h, decreased IgG levels at 24 h, and did not decrease the area under the curve (AUC) and IgG accumulation in main organs. Long-circulating BSA decreased IgG levels at 1 and 24 h, decreased the AUC, but did not significantly decrease organ accumulation. Long-circulating CLIO nanoworms increased IgG levels at 1 h, decreased IgG levels at 24 h, did not decrease the AUC, and did not decrease the organ accumulation. On the other hand, short-circulating CLIO nanoparticles decreased IgG levels at 1 and 24 h, significantly decreasing the AUC and accumulation in the main organs. Multiple doses of CLIO and BSA were not able to completely eliminate the antibody from blood, despite the click reactivity of the residual IgG, likely due to exchange of IgG between blood and tissue compartments. Pharmacokinetic modeling suggests that short antidote half-life and fast click reaction rate should result in higher IgG depletion efficiency. Short-circulating click-modified nanocarriers are the most effective antidotes for elimination of antibodies from blood. This study sets a stage for future development of antidotes based on nanomedicine.

Brain Iron Distribution after Multiple Doses of Ultra-small Superparamagnetic Iron Oxide Particles in Rats.

The purpose of this study is to determine the effects of high cumulative doses of ultra-small paramagnetic iron oxide (USPIO) used in neuroimaging studies. We intravenously administered 8 mg/kg of 2 USPIO compounds daily for 4 wk to male Sprague-Dawley rats (Crl:SD). Multiecho gradient-echo MRI, serum iron levels, and histology were performed at the end of dosing and after a 7-d washout period. R2* maps and quantitative susceptibility maps (QSM) were generated from multiecho gradient-echo data. R2* maps and QSM showed iron accumulation in brain ventricles on MR images acquired at the 4- and 5-wk time points. Estimates from QSM data showed ventricular iron concentration was equal to or higher than serum iron concentration. Histologic analysis revealed choroid plexus hemosiderosis and midbrain vacuolation, without iron deposition in brain parenchyma. Serum iron levels increased with administration of both compounds, and a 7-d washout period effectively reduced serum iron levels of one but not both of the compounds. High cumulative doses from multiple, frequent administrations of USPIO can lead to iron deposition in brain ventricles, resulting in persistent signal loss on T2*-weighted images. Techniques such as QSM are helpful in quantifying iron biodistribution in this situation.

Variability of Complement Response toward Preclinical and Clinical Nanocarriers in the General Population.

Opsonization (coating) of nanoparticles with complement C3 component is an important mechanism that triggers immune clearance and downstream anaphylactic and proinflammatory responses. The variability of complement C3 binding to nanoparticles in the general population has not been studied. We examined complement C3 binding to dextran superparamagnetic iron oxide nanoparticles (superparamagnetic iron oxide nanoworms, SPIO NWs, 58 and 110 nm) and clinically approved nanoparticles (carboxymethyl dextran iron oxide ferumoxytol (Feraheme, 28 nm), highly PEGylated liposomal doxorubicin (LipoDox, 88 nm), and minimally PEGylated liposomal irinotecan (Onivyde, 120 nm)) in sera from healthy human individuals. SPIO NWs had the highest variation in C3 binding (n = 47) between subjects, with a 15-30 fold range in levels of C3. LipoDox (n = 12) and Feraheme (n = 18) had the lowest levels of variation between subjects (an approximately 1.5-fold range), whereas Onivyde (n = 18) had intermediate between-subject variation (2-fold range). There was no statistical difference between males and females and no correlation with age. There was a significant correlation in complement response between small and large SPIO NWs, which are similar structurally and chemically, but the correlations between SPIO NWs and other types of nanoparticles, and between LipoDox and Onivyde, were not significant. The calculated average number of C3 molecules bound per nanoparticle correlated with the hydrodynamic diameter but was decreased in LipoDox, likely due to the PEG coating. The conclusions of this study are (1) all nanoparticles show variability of C3 opsonization in the general population; (2) an individual's response toward one nanoparticle cannot be reliably predicted based on another nanoparticle; and (3) the average number of C3 molecules per nanoparticle depends on size and surface coating. These results provide new strategies to improve nanomedicine safety.

SIRB, sans iron oxide rhodamine B, a novel cross-linked dextran nanoparticle, labels human neuroprogenitor and SH-SY5Y neuroblastoma cells and serves as a USPIO cell labeling control.

This is the first report of the synthesis of a new nanoparticle, sans iron oxide rhodamine B (SIRB), an example of a new class of nanoparticles. SIRB is designed to provide all of the cell labeling properties of the ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle Molday ION Rhodamine B (MIRB) without containing the iron oxide core. MIRB was developed to label cells and allow them to be tracked by MRI or to be manipulated by magnetic gradients. SIRB possesses a similar size, charge and cross-linked dextran coating as MIRB. Of great interest is understanding the biological and physiological changes in cells after they are labeled with a USPIO. Whether these effects are due to the iron oxide buried within the nanoparticle or to the surface coating surrounding the iron oxide core has not been considered previously. MIRB and SIRB represent an ideal pairing of nanoparticles to identify nanoparticle anatomy responsible for post-labeling cytotoxicity. Here we report the effects of SIRB labeling on the SH-SY5Y neuroblastoma cell line and primary human neuroprogenitor cells (hNPCs). These effects are contrasted with the effects of labeling SH-SY5Y cells and hNPCs with MIRB. We find that SIRB labeling, like MIRB labeling, (i) occurs without the use of transfection reagents, (ii) is packaged within lysosomes distributed within cell cytoplasm, (iii) is retained within cells with no loss of label after cell storage, and (iv) does not alter cellular viability or proliferation, and (v) SIRB labeled hNPCs differentiate normally into neurons or astrocytes. Copyright © 2016 John Wiley & Sons, Ltd.

Influenza vaccination in Austria from 1982 to 2011: a country resistant to influenza prevention and control.

BACKGROUND: Austria's position on influenza vaccination is unique. Generally it is recommended for everyone, and specifically for those over the age of 50 years and all children between 6 months and 5 years. However, the vaccination rate among the general public is one of the lowest in the world (<10%). Our objective was to provide baseline information to allow a better understanding of the low vaccination rate. METHODS: This paper presents data on influenza vaccine use in Austria during a period of almost 30 years, from 1982 to 2011. Data presented in this study were obtained from three sources. RESULTS: Between 1982 and 1992, Austria showed little change in its low proportion of vaccinations (from 20 to 23 doses/1000); from 1992 to 1995, the proportion increased to 52 doses/1000, retaining its status as one of the low-use countries. By 2003, the proportion had increased to 127 doses/1000, but Austria remained one of the three lowest-use Western European countries. Between 2007 and 2011/2012, a steady decrease to 81 doses/1000 was observed. CONCLUSION: The Austrian population, and parts of the medical system, have shown distinct ignorance regarding the prevention and control of influenza over past decades. Possible reasons for this development are discussed.

Predictors of short-term success in smoking cessation in relation to attendance at a smoking cessation program.

INTRODUCTION: The identification of individual characteristics that predict success in smoking cessation is necessary to improve the effectiveness of smoking cessation efforts. The aim of this study was to identify the factors that predict success in smoking cessation in people who attended 2, 3, 4, or 5 sessions of a smoking cessation program. METHODS: The participants comprised 2,471 people who attended at least 2 consultations during a 5-week smoking cessation program. Success in smoking cessation was defined as self-reported abstinence and having an exhaled carbon monoxide level ≤10 parts per million at the final consultation. Baseline characteristics were compared using univariate analysis of variance and the chi-square test. A stepwise multivariate logistic regression model was used to analyze the effect of baseline characteristics and the slopes of the withdrawal symptoms on the success in smoking cessation. RESULTS: Participating in a higher number of sessions gradually increased the chance of smoking cessation from 12.1% to 61.2% (p < .0001). Logistic regression analysis revealed that the independent predictors of success in smoking cessation were being male; low nicotine dependence; smoking few cigarettes per day at baseline; having no history of depression; having low values for craving for cigarettes, irritability, frustration, anger, or nocturnal awakening at baseline; decreased craving for cigarettes and restlessness with time; and use of nicotine replacement therapy (NRT). People who attended more sessions tended to be older. CONCLUSIONS: Attending more sessions of a smoking cessation program, NRT, and coping with withdrawal and psychosocial symptoms increases the chance of short-term success in smoking cessation.

Trends in mortality and mean age at death from lung cancer in Austria (1975-2007).

OBJECTIVE: To investigate trends in mortality and mean age at death from lung cancer (MADLC) compared to mean age at death from all causes (MAD) over the period 1975 - 2007 in Austria. Results are assessed with respect to secular trends in smoking habits. METHODS: MAD and MADLC were computed by year and gender as the expected value of a fitted Weibull distribution. Age-period-cohort effects on lung cancer death rates were estimated by hierarchical Poisson models. RESULTS: In females MADLC was on average about 2 years higher than in males and tended to decrease since the mid 1980s, while after the mid 1990s MADLC in males increased such that the difference between men and women shrank to about half a year in 2007. Females dying from lung cancer lost about 6 years of life during the late 1970s but more than 10 years after 2000, while males lost 2 years in the 1970s and 5 years after 2000. Males demonstrated a decreasing risk with increasing year of birth, with the exception of cohorts born during or immediately after the World Wars that showed peak relative risks (RR). Females did not show pronounced birth cohort effect except for a peak RR for cohorts born during and after World War II. CONCLUSIONS: MADLC provides additional information about secular trends in addition to incidence data. The declining trend of MADLC in females and in males up to the mid 1990s points to a change of smoking habits with an earlier onset of smoking in both genders. The subsequent increase in males during the last decade may be attributed to an increasing proportion of quitters because smoking cessation delays onset of lung cancer.

Estimation of glomerular filtration rate in dogs by plasma clearance of gadolinium diethylenetriamine pentaacetic acid as measured by use of an ELISA.

OBJECTIVE-To evaluate use of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) to estimate glomerular filtration rate (GFR) by plasma clearance and use of an ELISA as the method of Gd-DTPA quantification. ANIMALS-16 dogs of various sexes and breeds (12 dogs were clinically normal, and 4 dogs were polyuric and polydipsic with no other clinical or biochemical abnormalities). PROCEDURES-GFR was estimated by measuring the plasma clearance of Gd-DTPA and iohexol by use of an ELISA and high-performance liquid chromatography (HPLC), respectively. The GFR was determined by use of a 1-compartment model for both methods. The GFRs obtained by Gd-DTPA plasma clearance were compared with those obtained by iohexol plasma clearance by use of correlation analysis, paired t tests, and limits of agreement analysis. A paired t test was used to evaluate differences between the 2 plasma clearance methods. RESULTS-A strong linear correlation (r(2) = 0.90) was found between GFRs derived from the plasma clearance of Gd-DTPA and those derived from the plasma clearance of iohexol. By use of limits of agreement analysis, almost all (13/14) dogs had Gd-DTPA GFRs that were within 12% of iohexol GFRs. The remaining dog had a Gd-DTPA GFR that was 45% higher than the iohexol GFR. There was no significant difference between Gd-DTPA GFRs and those obtained with iohexol. CONCLUSIONS AND CLINICAL RELEVANCE-This study revealed that plasma clearance of Gd-DTPA measured by use of an ELISA is an effective method to estimate GFR in dogs because it compared favorably with results for the iohexol-HPLC method.