Associated Links Among Smoking, Chronic Obstructive Pulmonary Disease, and Small Cell Lung Cancer: A Pooled Analysis in the International Lung Cancer Consortium.

Background The high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention. Methods We included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity. Further, we explored whether the risk of smoking on SCLC was mediated through COPD. Findings Significant dose–response relationships of SCLC risk were observed for all quantitative smoking variables. Smoking pack-years were associated with a sharper increase of SCLC risk for pack-years ranged 0 to approximately 50. The former smokers with longer cessation showed a 43%quit_for_5–9 years to 89%quit_for_≥ 20 years declined SCLC risk vs. subjects who had quit smoking < 5 years. Compared with non-COPD subjects, smoking behaviors showed a significantly higher effect on SCLC risk among COPD subjects, and further, COPD patients showed a 1.86-fold higher risk of SCLC. Furthermore, smoking behaviors on SCLC risk were significantly mediated through COPD which accounted for 0.70% to 7.55% of total effects. Interpretation This is the largest pooling study that provides improved understanding of smoking on SCLC, and further demonstrates a causal pathway through COPD that warrants further experimental study. Abbreviations COPD, chronic obstructive pulmonary disease; CPG, cigarettes per day; ILCCO, International Lung Cancer Consortium; MeSH, medical subject headings; NSCLC, non-small cell lung cancer; OR, odds ratio; SCLC, small cell lung cancer

LDL-Induced Impairment of Human Vascular Smooth Muscle Cells Repair Function Is Reversed by HMG-CoA Reductase Inhibition

Growing human atherosclerotic plaques show a progressive loss of vascular smooth muscle cells (VSMC) becoming soft and vulnerable. Lipid loaded-VSMC show impaired vascular repair function and motility due to changes in cytoskeleton proteins involved in cell-migration. Clinical benefits of statins reducing coronary events have been related to repopulation of vulnerable plaques with VSMC. Here, we investigated whether HMG-CoA reductase inhibition with rosuvastatin can reverse the effects induced by atherogenic concentrations of LDL either in the native (nLDL) form or modified by aggregation (agLDL) on human VSMC motility. Using a model of wound repair, we showed that treatment of human coronary VSMC with rosuvastatin significantly prevented (and reversed) the inhibitory effect of nLDL and agLDL in the repair of the cell depleted areas. In addition, rosuvastatin significantly abolished the agLDL-induced dephosphorylation of myosin regulatory light chain as demonstrated by 2DE-electrophoresis and mass spectrometry. Besides, confocal microscopy showed that rosuvastatin enhances actin-cytoskeleton reorganization during lipid-loaded-VSMC attachment and spreading. The effects of rosuvastatin on actin-cytoskeleton dynamics and cell migration were dependent on ROCK-signalling. Furthermore, rosuvastatin caused a significant increase in RhoA-GTP in the cytosol of VSMC. Taken together, our study demonstrated that inhibition of HMG-CoA reductase restores the migratory capacity and repair function of VSMC that is impaired by native and aggregated LDL. This mechanism may contribute to the stabilization of lipid-rich atherosclerotic plaques afforded by statins

Mammographic density and ageing:A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was -0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (-0.38 cm [95% CI: -0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction

International Consortium on Mammographic Density:methodology and population diversity captured across 22 countries

Mammographic density (MD) is a quantitative trait, measurable in all women, and is among the strongest markers of breast cancer risk. The population-based epidemiology of MD has revealed genetic, lifestyle and societal/environmental determinants, but studies have largely been conducted in women with similar westernized lifestyles living in countries with high breast cancer incidence rates. To benefit from the heterogeneity in risk factors and their combinations worldwide, we created an International Consortium on Mammographic Density (ICMD) to pool individual-level epidemiological and MD data from general population studies worldwide. ICMD aims to characterize determinants of MD more precisely, and to evaluate whether they are consistent across populations worldwide. We included 11755 women, from 27 studies in 22 countries, on whom individual-level risk factor data were pooled and original mammographic images were re-read for ICMD to obtain standardized comparable MD data. In the present article, we present (i) the rationale for this consortium; (ii) characteristics of the studies and women included; and (iii) study methodology to obtain comparable MD data from original re-read films. We also highlight the risk factor heterogeneity captured by such an effort and, thus, the unique insight the pooled study promises to offer through wider exposure ranges, different confounding structures and enhanced power for sub-group analyses

Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

Peer reviewe

Vascular Remodeling in Health and Disease

The term vascular remodeling is commonly used to define the structural changes in blood vessel geometry that occur in response to long-term physiologic alterations in blood flow or in response to vessel wall injury brought about by trauma or underlying cardiovascular diseases.1, 2, 3, 4 The process of remodeling, which begins as an adaptive response to long-term hemodynamic alterations such as elevated shear stress or increased intravascular pressure, may eventually become maladaptive, leading to impaired vascular function. The vascular endothelium, owing to its location lining the lumen of blood vessels, plays a pivotal role in regulation of all aspects of vascular function and homeostasis.5 Thus, not surprisingly, endothelial dysfunction has been recognized as the harbinger of all major cardiovascular diseases such as hypertension, atherosclerosis, and diabetes.6, 7, 8 The endothelium elaborates a variety of substances that influence vascular tone and protect the vessel wall against inflammatory cell adhesion, thrombus formation, and vascular cell proliferation.8, 9, 10 Among the primary biologic mediators emanating from the endothelium is nitric oxide (NO) and the arachidonic acid metabolite prostacyclin [prostaglandin I2 (PGI2)], which exert powerful vasodilatory, antiadhesive, and antiproliferative effects in the vessel wall

Die Zwei-Umschläge-Methode für aktives Lernen

Purpose: Active learning improves knowledge acquisition and provides medical students with learning habits that become an integral part of their behavior. As an integral element of our institution's transition from a lecture hall teaching culture to active learning, the current project, conducted with fourth year students, aimed to examine the effects of the two envelopes method of teaching on students' knowledge. Method: The class of 120 students was divided into 12 groups of 10 students each. Six experienced senior cardiologists were assigned to teach the 12 groups. When the students arrived at the classroom, they received two envelopes. Students were instructed to open the first envelope and answer a 10-question test in 15 minutes. After completing the test, they returned the tests to the envelope, sealed it, and then opened the second envelope which included the same test and relevant patient information. They then spent the next 30 minutes discussing the test as a group and familiarizing themselves with the patients' case histories and clinical data. After completion of the group discussion, the tutor entered the room for a two-hour discussion of the patients' disease entities including the anatomy, physiology, pathology, clinical presentation, diagnostic measures, and potential therapies. Results: We compared grades and standard deviations of grades between two classes: one learned in the lecture hall format (2018) and the other learned employing the two-envelopes method (2019). There was a non-statistically significant trend toward better grades with reduced dispersion of grades in the class that learned with the two-envelope method. Conclusions: We describe a novel method for active learning that enhances self-learning and peer learning, and we observed better knowledge acquisition and reduced knowledge dispersion that were not statistically significant.Zweck der Studie: Aktives Lernen verbessert die Aneignung von Wissen und vermittelt Medizinstudierenden Lerngewohnheiten, die zu einem integralen Bestandteil ihrer Verhaltensweise werden. Das aktuelle Projekt wurde mit Studierenden im vierten Studienjahr durchgeführt und diente als wichtiges Element bei der Umstellung unserer Einrichtung von der bisherigen vorlesungsbasierten Lehrkultur zu einer aktiven Lernkultur und dazu, die Auswirkungen der Zwei-Umschläge-Methode auf die Kenntnisse der Studierenden zu untersuchen. Methode: Der Kurs mit 120 Studierenden wurde in 12 Gruppen mit je 10 Studierenden aufgeteilt. Sechs erfahrene Kardiologen wurden den 12 Gruppen als Lehrkräfte zugeteilt. Im Lehrsaal erhielten die Studierenden zwei Umschläge. Ihnen wurde aufgetragen, den ersten Umschlag zu öffnen und einen Test mit 10 Fragen innerhalb von 15 Minuten zu beantworten. Nach Abschluss des Tests steckten sie die Testbögen wieder in den Umschlag, verschlossen diesen und öffneten dann den zweiten Umschlag, in dem sich der gleiche Test mit relevanten Patienteninformationen befand. Sie verbrachten die nächsten 30 Minuten damit, den Test in der Gruppe zu besprechen und sich mit den Fallbeschreibungen und den klinischen Daten der Patienten zu befassen. Nach Abschluss der Gruppendiskussion betrat eine Lehrkraft den Raum für eine zweistündige Besprechung der Krankheitsbilder der Patienten, einschließlich der Anatomie, Physiologie, Pathologie sowie der klinischen Erscheinungsbilder, diagnostischen Maßnahmen und potenziellen Therapien. Ergebnis: Wir verglichen die Ergebnisse und Standardabweichungen durch die Noten der beiden Kurse. Der eine Kurs wurde in Form von Vorlesungen unterrichtet (2018), der andere Kurs erlernte die Anwendung der Zwei-Umschläge-Methode (2019). Im Kurs mit der Zwei-Umschläge-Methode waren die Noten ohne statistische Signifikanz tendenziell besser und die Notenstreuung tendenziell kleiner. Fazit: Wir beschreiben eine neuartige Methode für aktives Lernen, die eigenständiges Lernen und kollegiales Lernen in der Gruppe (peer learning) fördert, und beobachteten einen besseren Erwerb von Wissen und geringere Abweichungen im Wissensstand, ohne statistische Signifikanz