The clinical use of genetic analyses in colorectal cancer

Background: Colorectal cancer (CRC) is a common global disease, with a mortality rate of almost 50%. Prognosis is mainly based on the TNM classification. Surgical interventions have the potential of being curative in patients with stage I-III CRC. Adjuvant treatment with chemotherapy enhances the survival rate, especially in stage III cancer. Chemotherapy does, however, have significant side effects. Therefore, refinement of therapies based on improved prognostic ability on an individual level is essential. One way to achieve this could be to examine the tumours on a molecular level and not just histologically. Recent studies have shown that K-ras mutation is a negative predictor to anti-EGFR (epidermal growth factor receptor) therapy. MicroRNAs were discovered only 2 decades ago but are now the most promising biomarkers in many cancers. In this thesis, the first two papers focus on genetic changes in the tumour and in lymph nodes, in particular looking at the oncogene K-ras. The last two papers focus on microRNAs in tumours and in blood serum. In studies 2, 3 and 4, our findings on the correlation of some molecular changes to prognosis is described. Study I: 17 tumours from CRC patients were divided in to small cubes. DNA was extracted from each biopsy and the occurrence of K-ras mutations, methylation of p16 and MGMT, and loss of heterozygosity (LOH) at 5q, 17p and 18q were analysed. We found that the distribution of methylated p16 and MGMT and LOH at 5q, 17 p and 18q are heterogeneous and present in a large majority of CRC tumours, thereby of limited prognostic value. However, K-ras mutation appears more homogeneously spread, a finding of clinical relevance for the use of biopsies to predict anti-EGFR response. Study II: 99 stage II CRC patients with histologically normal lymph nodes were included. DNA was extracted from lymph nodes, tumours and normal mucosa and the K-ras status was analysed and correlated to prognosis. Of the tumours, 34/99 were identified as positive for K-ras mutations. Of these, 10 patients also expressed K-ras mutations in their lymph nodes. Of the 10 patients with positive lymph nodes, 7 (70%) relapsed and died from the disease within 60 months compared to 8/ 24 (33%) with K-ras negative lymph nodes. Study III: 50 CRC patients were studied. RNA was extracted from the tumours. 5 patients with short and 5 patients with long survival were selected for SYBR-green quantitative PCR-based array to screen for differently expressed microRNAs. From this screening, 6 candidate prognostic microRNAs were validated using TaqMan quantitative PCR in all 50 patients. We found that high expression of miR-185 and low expression of miR-133b correlated to poor survival (p=0.001 and p=0.028, respectively) and metastasis (p=0.007 and p=0.036, respectively) in CRC. Study IV: 16 CRC patients and one with a large adenoma in the colon were included. All patients underwent radical (R0) surgery. Blood serum was collected prior to and 30 days after surgery. 3 microRNAs were analysed with Taqman qPCR (miR-21, miR-133b and miR-185). The serum levels of mir-21 were not affected by radical tumour resection. There was a significant decrease in the level of miR-133b among the patients following surgery, and an overall reduction of miR-185. There was no correlation between intra-individual changes in serum levels pre- and postoperatively to disease outcome, or between baseline levels and the risk of recurrent disease

European Society of Cardiology: Cardiovascular Disease Statistics 2017

Background: The European Society of Cardiology (ESC) Atlas has been compiled by the European Heart Agency to document cardiovascular disease (CVD) statistics of the 56 ESC member countries. A major aim of this 2017 data presentation has been to compare high income and middle income ESC member countries, in order to identify inequalities in disease burden, outcomes and service provision. Methods: The Atlas utilizes a variety of data sources, including the World Health Organization, the Institute for Health Metrics and Evaluation, and the World Bank to document risk factors, prevalence and mortality of cardiovascular disease and national economic indicators. It also includes novel ESC sponsored survey data of health infrastructure and cardiovascular service provision provided by the national societies of the ESC member countries. Data presentation is descriptive with no attempt to attach statistical significance to differences observed in stratified analyses. Results: Important differences were identified between the high income and middle income member countries of the ESC with regard to CVD risk factors, disease incidence and mortality. For both women and men, the age-standardised prevalence of hypertension was lower in high income countries (18.3% and 27.3%) compared with middle income countries (23.5% and 30.3%). Smoking prevalence in men (not women) was also lower (26% vs 41.3%), and together these inequalities are likely to have contributed to the higher CVD mortality in middle income countries. Declines in CVD mortality have seen cancer becoming a more common cause of death in a number of high income member countries, but in middle income countries declines in CVD mortality have been less consistent where CVD remains the leading cause of death. Inequalities in CVD mortality are emphasised by the smaller contribution they make to potential years of life lost in high income compared with middle income countries both for women (13% vs. 23%) and men (20% vs. 27%). The downward mortality trends for CVD may, however, be threatened by the emerging obesity epidemic that is seeing rates of diabetes increasing across all ESC member countries. Survey data from the National Cardiac Societies (n=41) showed that rates of cardiac catheterization and coronary artery bypass surgery, as well as the number of specialist centres required to deliver them, were greatest in the high income member countries of the ESC. The Atlas confirmed that these ESC member countries, where the facilities for the contemporary treatment of coronary disease were best developed, were often those in which declines in coronary mortality have been most pronounced. Economic resources were not the only driver for delivery of equitable cardiovascular healthcare, as some middle income ESC member countries reported rates for interventional procedures and device implantations that matched or exceeded the rates in wealthier member countries. Conclusion: In documenting national CVD statistics, the Atlas provides valuable insights into the inequalities in risk factors, healthcare delivery and outcomes of CVD across ESC member countries. The availability of these data will underpin the ESC’s ambitious mission “to reduce the burden of cardiovascular disease” not only in its member countries, but also in nation states around the world

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Rule-Based Models of the Interplay between Genetic and Environmental Factors in Childhood Allergy

Peer reviewe

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity . Here we use 2,009\ua0population-based studies, with measurements of height and weight in more than 112\ua0million adults, to report national, regional and global trends in mean\ua0BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in\ua0some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities\ua0in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

En jämförande fallstudie av kundlojalitetsprocesserna hos konfektionsföretagen Gul&Blå och Sixty Sverige.

Dagens konfektionsmarknad präglas av hård konkurrens, vilket innebär att småföretag inte enbart kan konkurrera med produktkvalitet och flertalet företag vill inte konkurrera med pris. Detta ökar vikten av gedigen kundförståelse, förmåga att identifiera och lösa kundens behov samt att skapa värden för kunden. För en märkesinnehavare är det yttersta målet kundlojalitet då det leder till långsiktiga kundrelationer. Denna uppsats behandlar de olika faktorerna i en process med målet att skapa kundlojalitet, som är viktiga för att småföretag ska kunna överleva (vara lönsamma), på den alltmer konkurrensutsatta marknaden. Sveriges modebransch utgörs till största delen av småföretag. Småföretagen är väldigt dominerade av storföretagen som genom stordriftfördelar och uppgång i internationella företagskonstellationer kan sätta villkoren för småföretagsamheten och avgöra vilken sorts företag som kan överleva på marknaden. Den svenska småföretagarens relativa position har försvagats och för små svenska jeansföretag innebär det en stor utmaning att överleva, behålla sina kunder och vara lönsamma. Detta ökar vikten av att den så kallade kundlojalitetsprocessen hos företagen är optimal. Syftet med uppsatsen är, att med en jämförande fallstudie, utvärdera kundlojalitetsprocesserna hos konfektionsföretagen Gul&Blå och Sixty Sverige för varumärkena Gul&Blå och Miss Sixty. För att undersöka det valda området, utförs djupintervjuer med respektive jeansföretag. Teorier som uppsatsen bygger på är varumärkesuppbyggnad, engagemang, upplevd risk, styrningsmetoderna mål- och processtyrning samt perspektiven transaktions- och relationsmarknadsföring. Undersökningen visar att kundlojalitetsprocessen är optimal när förtaget använder sig av samtliga aktiviteter i den varumärkesuppbyggande processen, arbetar för att minimera kundens upplevda risk gentemot produkterna, ökar engagemanget för produkterna genom säljfrämjande åtgärder, arbetar processtyrt samt arbetar enligt perspektivet om relationsmarknadsföring. Nyckelord: kundlojalitet, varumärkesuppbyggnad, upplevd risk, engagemang, processtyrning, relationsmarknadsföring

En jämförande fallstudie av kundlojalitetsprocesserna hos konfektionsföretagen Gul&Blå och Sixty Sverige.

Dagens konfektionsmarknad präglas av hård konkurrens, vilket innebär att småföretag inte enbart kan konkurrera med produktkvalitet och flertalet företag vill inte konkurrera med pris. Detta ökar vikten av gedigen kundförståelse, förmåga att identifiera och lösa kundens behov samt att skapa värden för kunden. För en märkesinnehavare är det yttersta målet kundlojalitet då det leder till långsiktiga kundrelationer. Denna uppsats behandlar de olika faktorerna i en process med målet att skapa kundlojalitet, som är viktiga för att småföretag ska kunna överleva (vara lönsamma), på den alltmer konkurrensutsatta marknaden. Sveriges modebransch utgörs till största delen av småföretag. Småföretagen är väldigt dominerade av storföretagen som genom stordriftfördelar och uppgång i internationella företagskonstellationer kan sätta villkoren för småföretagsamheten och avgöra vilken sorts företag som kan överleva på marknaden. Den svenska småföretagarens relativa position har försvagats och för små svenska jeansföretag innebär det en stor utmaning att överleva, behålla sina kunder och vara lönsamma. Detta ökar vikten av att den så kallade kundlojalitetsprocessen hos företagen är optimal. Syftet med uppsatsen är, att med en jämförande fallstudie, utvärdera kundlojalitetsprocesserna hos konfektionsföretagen Gul&Blå och Sixty Sverige för varumärkena Gul&Blå och Miss Sixty. För att undersöka det valda området, utförs djupintervjuer med respektive jeansföretag. Teorier som uppsatsen bygger på är varumärkesuppbyggnad, engagemang, upplevd risk, styrningsmetoderna mål- och processtyrning samt perspektiven transaktions- och relationsmarknadsföring. Undersökningen visar att kundlojalitetsprocessen är optimal när förtaget använder sig av samtliga aktiviteter i den varumärkesuppbyggande processen, arbetar för att minimera kundens upplevda risk gentemot produkterna, ökar engagemanget för produkterna genom säljfrämjande åtgärder, arbetar processtyrt samt arbetar enligt perspektivet om relationsmarknadsföring. Nyckelord: kundlojalitet, varumärkesuppbyggnad, upplevd risk, engagemang, processtyrning, relationsmarknadsföring