Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis

Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93–80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.</p

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 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3�6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI 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 some 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 in 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. © 2019, The Author(s)

A century of trends in adult human height

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5-22.7) and 16.5 cm (13.3-19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8-144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol�which is a marker of cardiovascular risk�changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95 credible interval 3.7 million�4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world. © 2020, The Author(s), under exclusive licence to Springer Nature Limited

Biomarkers in atopic dermatitis

Main findings of this thesis · A meta-analysis including 222 studies showed that serum TARC level is the best biomarker for disease severity currently available (chapter 2). · Immunoglobulin free light chains have been shown to correlate with disease severity in paediatric AD. However, they do not correlate with disease severity in adult AD (chapter 6). · A pilot study in 17 AD patients showed that a combination of serum biomarkers is better in assessing disease severity than a single biomarker (chapter 3). · In a prospective cohort of 200 patients it was shown that combining serum TARC, IL-22 and sIL-2R levels in an algorithm accurately predicts clinically measured disease severity (predicted EASI) in 90% of AD patient treated with topical steroids (chapter 4). · The p-EASI also predicts disease severity in patients treated with cyclosporin A (chapter 5). · The p-EASI offers an objective outcome measure for disease severity in prospective AD studies (chapter 4 and 5). Biomarkers enabling precision medicine in atopic dermatitis · High expression levels of circulating inflammatory biomarkers suggest that AD is a systemic disease. Recently described comorbidities may be the result of this systemic inflammation, and emphasize the need for a multidisciplinary approach for optimal management of AD and its comorbidities (chapter 9) · AD is a heterogeneous disease both clinically and biologically. We have identified four clusters of AD patients based on specific serum biomarker profiles, implying that each of these clusters is driven by a distinct underlying pathway and these clusters may represent different endotypes (chapter 7). · UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to mycophenolic acid therapy, thereby showing the potential of pharmacodynamic biomarkers in AD (chapter 8). Improving practical aspects of biomarker measurement · The biomarkers studied in this thesis are measured in serum. However, multiple other sources for biomarker measurement exist, for instance saliva and dried blood spots (chapter 10). · A disadvantage of the use of serum biomarkers is the need for a venipuncture. TARC levels measured in dried blood spots also highly correlate with disease severity and significantly decrease during effective treatment. Therefore, dried blood spots may offer a simple and minimally invasive method for measurement of biomarkers in AD (chapter 11)

Biomarkers in atopic dermatitis

Main findings of this thesis · A meta-analysis including 222 studies showed that serum TARC level is the best biomarker for disease severity currently available (chapter 2). · Immunoglobulin free light chains have been shown to correlate with disease severity in paediatric AD. However, they do not correlate with disease severity in adult AD (chapter 6). · A pilot study in 17 AD patients showed that a combination of serum biomarkers is better in assessing disease severity than a single biomarker (chapter 3). · In a prospective cohort of 200 patients it was shown that combining serum TARC, IL-22 and sIL-2R levels in an algorithm accurately predicts clinically measured disease severity (predicted EASI) in 90% of AD patient treated with topical steroids (chapter 4). · The p-EASI also predicts disease severity in patients treated with cyclosporin A (chapter 5). · The p-EASI offers an objective outcome measure for disease severity in prospective AD studies (chapter 4 and 5). Biomarkers enabling precision medicine in atopic dermatitis · High expression levels of circulating inflammatory biomarkers suggest that AD is a systemic disease. Recently described comorbidities may be the result of this systemic inflammation, and emphasize the need for a multidisciplinary approach for optimal management of AD and its comorbidities (chapter 9) · AD is a heterogeneous disease both clinically and biologically. We have identified four clusters of AD patients based on specific serum biomarker profiles, implying that each of these clusters is driven by a distinct underlying pathway and these clusters may represent different endotypes (chapter 7). · UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to mycophenolic acid therapy, thereby showing the potential of pharmacodynamic biomarkers in AD (chapter 8). Improving practical aspects of biomarker measurement · The biomarkers studied in this thesis are measured in serum. However, multiple other sources for biomarker measurement exist, for instance saliva and dried blood spots (chapter 10). · A disadvantage of the use of serum biomarkers is the need for a venipuncture. TARC levels measured in dried blood spots also highly correlate with disease severity and significantly decrease during effective treatment. Therefore, dried blood spots may offer a simple and minimally invasive method for measurement of biomarkers in AD (chapter 11)