Mistakes in mouse models of NASH and how to avoid them

Several animal models attempt to mirror each stage of human NAFLD

Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease worldwide that can manifest as nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH). Compared with NAFL, NASH poses a substantially higher risk of progression to advanced liver disease, cirrhosis and hepatocellular carcinoma (HCC). Given the lack of directed pharmacological therapies and the complex, multifactorial disease aetiology and pathology, NAFLD is expected to become the leading cause of end-stage liver disease in the coming decades.

Preclinical research aimed at elucidating the molecular mechanisms driving disease and identifying reliable biomarkers and potential treatments is critical and has gained significant attention in recent years. Several animal models attempt to mirror the histopathology and pathophysiology of each stage of human NAFLD, including the development of NASH and fibrosis, up to HCC development. Most in vivo studies use mouse models owing to their relatively low cost, short lifespan and ease of genetic manipulation, which allow for a level of experimental control that is not possible with human studies. Independent of each model’s inherent advantages and disadvantages, making a mistake when choosing, performing, or even analyzing results for a particular animal NASH model may jeopardize our ability to obtain accurate results or draw firm conclusions. 
Here, we discuss some mistakes commonly made in NASH preclinical research. We also consider the challenges and opportunities when selecting animal models for the study of NAFLD.

GI Hive, a brand new blog by the UEG Young Talent Group

Yasmijn van Herwaarden reveals more about the activities of young GIs within UEG. 

GI Hive is a brand new blog edited by UEG Young Talent Group that combines the most up-to-date information about life, career development, education and opportunities for young GI specialists in Europe. Interviews, infographics, WhatsApp conversations and videos with both junior and renowned specialists will be regularly published in GI Hive.

The first bee in the GI Hive is Yasmijn van Herwaarden – UEG Young Talent Group (YTG) chair. Yasmijn is a resident at the Rijnstate hospital in Arnhem, the Netherlands and tries to finish her PhD thesis at the Radboud university hospital in Nijmegen. She is a 30-year old Sagittarius and loves painting, pilates and plants. 

Yasmijn, could you explain what is exactly Young Talent Group? What are the activities of the young GIs within UEG?

The Young Talent Group (YTG) was formed under the umbrella of the National Societies Committee to make the UEG and especially UEG Week more accessible and attractive for young specialists, residents, PhD students and post-docs working in digestive diseases. 
Within the YTG we are a group of nine from all over Europe who meet twice a year to plan our activities. We have a young representative in all other UEG committees to give the young perspective on all UEG activities. Next to the YTG we try to have a “friend of the YTG” in each national society connected to UEG. These Friends are our ambassadors and inform us on issues and activities from their country and they spread the word about our activities in each country. 
An important part of our activities take place during the UEG Week. We try to help guide first time visitors to the congress with for example the Young GI track in the congress app and the popular mentoring program. 
We try to facilitate informal networking in the young GI lounge were everyone under 40 is welcome for coffee and power outlets during the whole week and by organizing the Let’s Meet event on Sunday night each year. We also organize special sessions for young GI’s, for example this years “How to prepare a presentation” and the “Check your CV” informal meeting in the lounge. 

Among the most popular opportunities provided by YTG are the clinical and research fellowship programmes. Could you share with us a little bit more about them?

These fellowships were started to give young clinicians and researchers an opportunity to visit another European centre. We award € 1250 to spend at least two weeks in one of the participating centers. 
When rating the applications for this fellowship we are looking for young people with a specific plan of what they want to learn from the centre they will be visiting. So if you want to apply please make a good plan of what you want to learn and carefully pick the center you want to visit to match your plan. 
This year we completely changed the research fellowship compared to the previous years. We will be awarding more money, € 50.000, to spend 12 months with a European principal investigator to work on a research project. We want to support new and longer lasting research collaborations with this fellowship. 
You have to propose a plan of what you want to do and choose the principal investigator you want to visit. Of course you can draw inspiration from the list of centers participating in the clinical fellowships.

The YTG published a paper on the needs of young GI sections in UEG Journal. Can you explain what are the needs of young sections belonging to UEG National Societies?

We circulated a questionnaire among our Friends of the Young Talent Group to make an overview of the situation of young GI’s in each country. We learned that in many countries the young GI’s/residents are not organized and represented at a national level. We believe that it is important for young professionals to be represented and actually have a say in decisions that are made about their daily work and their future workplace. 
We are trying to help the young GI’s in different countries to get organized and have a young representative in the National Society. We already have some success stories, for example the newly formed young GI sections in Bulgaria and Spain. 

Why it is important for a young GI to send an abstract to UEG Week? 

For me submitting an abstract as a young researcher was always important because it was the opportunity to visit a conference and travel. I was fortunate that if the abstract was accepted for poster or oral presentation my department would pay for the travel costs and the conference fee. 
I always get new inspiration and also motivation to continue my research after a conference. Even during a poster presentation I have gotten tips from the audience that would make it into the final manuscript. But it is also just a lot of fun to visit another country with colleagues and make new friends. 

How can a young GI get involved with Young Talent Group and what is Young GI Network?

An easy way to stay in touch and hear about all our offers is to like the Young GI Network Facebook page. You can also subscribe to our mailing list and visit the UEG website to hear about the open calls we post. All the calls for the fellowships, other awards and grants and open calls for new positions in the YTG will be posted there. 
Very soon we will start offering a new way to get involved in the UEG: it will become possible to actively apply for our new UEG Talent Pool. From this pool we will actively promote young talents to all the UEG committees. 
The last two years we did a pilot for the talent pool with the Scientific Committee where young researchers could volunteer to chair a UEG Week session together with a senior chair. The reactions from both the junior chairs and the Scientific Committee were very positive seeing this as an excellent opportunity. We will post more information shortly and open the application on the UEG website.

Interviewer: Radislav Nakov

Interdisciplinary cases combined with questions of diagnosis and therapy

The Evidence Based Medicine Course takes place during UEG Week 2019 in Barcelona.
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Mistakes in small bowel bleeding and how to avoid them

Definitive management of small bowel bleeding can pose formidable challenges

Over the past 17 years, the disruptive impact of technologies including small bowel capsule endoscopy (SBCE), device-assisted enteroscopy (DAE) and dedicated cross-sectional imaging has transformed the investigation and management of small bowel pathology. Although a small bowel source only accounts for 5–10% of all cases of gastrointestinal bleeding,1–2 definitive management of small bowel bleeding even in the current era of advanced imaging, can still pose formidable challenges.  

In this brief article, we highlight frequent mistakes made in the investigation and management of small bowel bleeding and discuss strategies for their avoidance. 

Check out our repository 

Guidance for your daily practice including consensus, position papers and standard protocols.

Basic and translational research in epithelial ion transport in the GI tract

A course for young PhDs and basic science oriented MDs with state-of-the-art lectures and hands-on lab training.
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Summer School in Prague 

This intense, clinically-oriented course is an educational concept for gastroenterology trainees, combining state-of-the-art lectures with practical skills training.
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Mistakes in acute jaundice and how to avoid them

Jaundice—one of the major signs in medicine—can result from numerous conditions

Jaundice or icterus (derived from the ancient Greek word ikteros that described the yellow-breasted oriole bird) is not a diagnosis in itself but constitutes one of the major signs in medicine. Jaundice refers to the yellowish discoloration of tissue that occurs as a consequence of the deposition of bilirubin. This discoloration is a physical manifestation of a marked increase in serum bilirubin levels. Normal serum bilirubin values are <17 μmol/L; for jaundice to be perceived visually serum bilirubin levels need to be elevated to >40 μmol/L (equivalent to 2.5 mg/dL).

Most serum bilirubin is formed from the breakdown of the haem contained in senescent red blood cells by the reticuloendothelial system. Thus, unconjugated bilirubin is released in the bloodstream, where it is bound by albumin. Through the blood circulation bilirubin is moved to liver hepatocytes, where it undergoes further processing. In brief, bilirubin becomes conjugated in the hepatocytes through glucuronidation, which allows it to be excreted from the body (unconjugated bilirubin is water insoluble and cannot pass into the urine). Conjugated bilirubin forms one of the main components of bile and most of it passes through the biliary tree to the intestine. Unconjugated and conjugated bilirubin are reported in laboratory measurements as indirect and direct bilirubin, according to their chemical properties (i.e. reaction with reagents).1 Jaundice can be caused by abnormalities in any of the steps comprising the formation, metabolism and excretion of bilirubin. In addition, these processes may be functioning properly, but jaundice can be seen because of an obstruction of the biliary tree at any point, from its intrahepatic origins to its end at the ampulla of Vater. For this reason, it is clear that numerous conditions can result in jaundice. When faced with a patient presenting with jaundice a reasonable and careful diagnostic approach is, therefore, warranted to elucidate the underlying cause of this sign. Conventional wisdom may be that “jaundice by itself never killed anyone,” but it is imperative to find the cause as soon as possible, as prompt intervention saves lives in many cases.  Here, we outline several of the mistakes made when approaching a patient presenting with acute jaundice based on our clinical experience and published data. 

Hereditary Gastrointestinal Polyposis Syndromes

Improve your understanding of Hereditary Gastrointestinal Polyposis Syndromes

Mistakes in capsule endoscopy and how to avoid them

Wireless technology means capsule endoscopy is well tolerated, but it is also a drawback

Capsule endoscopy is a noninvasive technique intended for studying the small bowel and/or colon. The capsule endoscope consists of a small, wireless, pill-sized camera that can be swallowed and allows direct visualization of the gastrointestinal mucosa. The design of the capsule differs depending on the part of the gastrointestinal tract to be studied. The small-bowel capsule has one optical dome and is generally used in patients who have suspected bleeding or to identify evidence of active Crohn’s disease. By contrast, the colon capsule has two optical domes, a higher frame rate and can be considered as an alternative to conventional colonoscopy, especially for cases when the examination was incomplete. There is also a new capsule with two optical domes that is designed for the panendoscopic study of both the small bowel and colon. 

The main characteristic of capsule endoscopy is the wireless technology, which enables it to be very well tolerated. However, this feature is also one of its drawbacks, as the capsule cannot be directly controlled by the physician. The capsule moves through the gut depending solely on intestinal motility, and the examiner is not able to drive it back and forth or to stop it to look more carefully at any finding. Moreover, the visualization relies heavily on the adequacy of intestinal cleansing as rinsing with water and aspiration are not possible. Capsule endoscopists should be aware of these shortcomings, as they directly affect the reading and diagnosis. Here we discuss frequent errors that are made when performing capsule endoscopy, based on the published literature and more than 15 years’ experience

A not-so-black-and-white case of gastrointestinal bleeding

What's causing the black tarry stool, episode of coffee-ground emesis and epigastric pain?

A 60-year-old woman presents at the Emergency Department complaining that she has been passing black, tarry stool since yesterday and had an episode of coffee-ground emesis some hours ago. It is the first time she has noticed these kinds of symptoms. Moreover, she reports episodes of epigastric pain on and off during the past week.

The patient has never undergone endoscopy. Her medical history includes diabetes mellitus, hypertension, hyperlipidaemia, gastro-oesophageal reflux disease (GORD), osteoarthritis and alcohol abuse. She admits that she occasionally uses nonsteroidal anti-inflammatory drugs (NSAIDs) to cope with episodes of pain caused by her osteoarthritis and that she took some in the past week. On physical examination she is tachycardic (92 beats per minute) and hypotensive (82/57 mm Hg), but afebrile and her oxygen saturation level is normal. Her abdomen is mildly distended, with some tenderness during deep palpation and increased bowel sounds. Her blood test results at presentation are shown in Table 1. A variceal bleed was suspected, and an emergency upper gastrointestinal endoscopy was performed (see video).   Case Question 1  WHAT IS YOUR CLINICAL DIAGNOSIS? A. Oesophageal melanoma
B. Oesophageal infection (e.g. CMV, HSV, Candidiasis)
C. Acanthosis nigricans
A. Diabetes mellitus
B. NSAID use
C. Alcohol abuse 
D. Hypoalbuminemia
E. Hypertension
A. Nil per os
B. Aggressive fluid resuscitation
C. Antibiotics 
D. IV acid suppression with PPIs
E. Glycaemic control

Personalised nutrition - food for thought

Developing tailored eating advice based on individual nutritional needs

‘Personalised nutrition’ represents any attempt to provide tailor-made healthy eating advice based on the nutritional needs of an individual, as dictated by their behaviour, phenotype and/or genotype and their interactions. Increasing evidence has shown the potential for integrating lifestyle habits, physiology, nutraceuticals, the gut microbiome and genetics into nutritional solutions, specific to the needs of each individual, for maintaining health and preventing disease. 

One area that has been gaining attention among both health professionals and the general public is nutrigenomics - the role of nutrients in gene expression. On a molecular level, nutrients work as messengers, transmitting signals that can be translated into changes in gene, protein, and metabolite expression and function, which may ultimately affect health outcomes. By employing molecular tools, nutrigenomics research identifies how nutrients and bioactive food compounds may alter gene expression, ultimately helping us to understand why people respond differently to the same diet and how genes and diet interact and predispose us to disease. 
Advances in nutrigenetics - how genes impact nutrient metabolism - and nutrigenomics do seem to encourage more personalised advice when it comes to food intake and nutritional supplements.1 
We are used to receiving generalized dietary guidelines and specific recommendations on food intake and nutrient supplements, based on age, gender and other requirements (e.g. during pregnancy or times of illness). For instance, many people will - at least intuitively - be familiar with some of the following daily nutritional recommendations for adults2:
  • 200 µg folic acid
  • 40 mg vitamin C
  • No more than 6 g salt
  • At least five portions of a variety of fruit and vegetables
  • No more than 11% of energy from saturated fat
Deficiencies in calcium, potassium, dietary fibre and vitamin D are also generally considered a public health concern.3 Some supplementation can be recommended. For example, folic acid taken during pregnancy to reduce the risk of malformations developing in the brain and spinal cord of the unborn child.  
By using information obtained from whole genome analysis, an individual’s genome can be scanned for polymorphisms (usually referred to as single nucleotide polymorphisms [SNPs]) in genes related to nutrient metabolism and disease development. For example, the methylenetetrahydrofolate reductase gene is associated with folate metabolism. If the common 677C-->T mutation (also known as the A222V mutation) is present in the methylenetetrahydrofolate reductase gene, it can result in an enzyme that has reduced activity. Should a person’s diet be low in folate, the presence of the 677C-->T mutation may lead to an increased risk of elevated homocysteine levels and a further moderate risk of cardiovascular disease.4,5 On a similar note, genetic variation may, at least in part, explain interindividual differences in plasma triacylglycerol concentrations on administration of polyunsatuared fatty acids, such as those found in fish oil,6 and it may also help explain why vitamin D might confer an increased risk of cancer development in some, while decreasing the risk in others.7 
So, is the future of gut (and general) health in personalised nutrition? How can we test it? Evidence-based medicine (EBM) relies on findings from randomized controlled trials to identify whether or not a given treatment or behaviour leads to a certain outcome. We have become used to EBM being critical to medical decision-making. A one-size-fits-all approach may appear inherently incompatible with the concept of personalised nutrition, and challenges arise when agreeing on the extent, quality and interpretation of evidence and consequent implications for dietary recommendations, particularly within the nutrigenomics arena. 
When will nutritional research be ready to be translated into public health action? Will personalized nutrition produce greater behaviour change and gains in health and wellbeing than can be achieved by conventional dietary advice?6 Although lowering the levels of dietary salt and saturated fats has had a positive effect on hypertension and lipid profiles, as demonstrated in clinical trials in healthy populations, limited trial data exist that prove a cause–effect relationship and a consequent reduction in disease by these dietary interventions.6 We also need to keep in mind that genes work together and not in isolation. This means that the presence of one SNP needs to be interpreted in the context of a person’s overall biochemistry, nutrition, and other lifestyle factors, such as activity, sleep and stress.
With advances in genetic testing, public awareness of personal genome testing and its potential is increasing. Companies are now offering affordable genetic testing options directly to the public. While there may be benefits to having your genetic information available, including the potential for personalised nutrition, there are also many risks and limitations that need to be highlighted and considered. These include, but are not limited to, whether there are sufficient regulations imposed on companies who perform genetic testing, interpretation and delivery of genetic information (via guidance of a health professional), ethical and social concerns, and privacy in terms of how DNA information is stored and used. 
Nutrigenomics and nutrigenetics, albeit an exciting area, is still relatively young and has not advanced enough to allow us to develop a diet based on a person’s entire genome–much more work is required before this can happen. Nonetheless, these tools have developed enough to highlight some nutrient–gene (and environment) interactions. So, for now, our advice is to watch this space as the field of personalised nutrition research continues to develop - who knows where we will find ourselves in the years to come!
Before you go, we would also like to guide your attention to the nutrition guidelines that are available in the UEG Standards & Guidelines Repository, including many from ESPEN and ESPGHAN! 
  1. Fenech M, El-Sohemy A, Cahill L, et al. Nutrigenetics and nutrigenomics: Viewpoints on the current status and applications in nutrition research and practice. J Nutrigenet Nutrigenom 2011; 4: 69–89.
  2. Food Standards Agency. Nutrient and food based guidelines for UK institutions. https://www.ptdirect.com/training-design/nutrition/national-nutrition-guidelines-united-kingdom. (2007, revised October 2007, accessed 11 May 2018).
  3. Blumeberg JF, Bailey RL, Sesso HD, et al. The evolving role of multivitamin/multimineral supplement use among adults in the age of personalized nutrition. Nutrients 2018; 10: 248. 
  4. Kohlmeier M, De Caterina R, Ferguson LR, et al. Guide and position of the International Society of Nutrigenetics/Nutrigenomics on personalized nutrition: Part 2 – Ethics, challenges and endeavors of Precision Nutrition. J Nutrigenet Nutrigenom 2016; 9: 28–46.
  5. Liew SC and Gupta ED. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: Epidemiology, metabolism and the associated diseases. Eur J Med Genet 2015; 58: 1–10.
  6. Görman U, Mathers JC, Grimaldi KA, et al. Do we know enough? A scientific and ethical analysis of the basis for genetic-based personalized nutrition. Genes Nutr 2013; 8: 373–381.
  7. Davis CD and Milner JA. Nutrigenomics, vitamin D and cancer prevention. J Nutrigenet Nutrigenom 2011; 4: 1–11.

This was Basic Science Course 2018

Read what happened this year or watch the recordings to learn about research in motility & neurogastroenterology.

Please sign-in and access the BORN module to begin interactive web-based training for endoscopists in the detection and delineation of Barrett´s Oesophagus Related Neoplasia now.

Over the last decade this training module has been developed and validated by members of the International Working Group for the Classification of Oesophagitis.
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This was Summer School 2018

158 trainees from 29 countries met for a weekend full of lectures and hands-on training.

Mistakes in clinical investigation of gastrointestinal motility & function

Symptoms related to abnormal motility and function are very common.

Symptoms related to abnormal gastrointestinal motility and function can occur from the moment food is swallowed to the time stool is passed into the toilet. A recent UEG survey indicated that dysphagia, heartburn, bloating, abdominal pain and changes to bowel habit are each reported by 5–15% of the general population.1 These symptoms are frequent reasons for seeking medical attention from general physicians and for referral to specialist gastroenterologists. Most patients with these symptoms do not have neoplasia, infection or inflammation on initial investigation, but rather so-called functional gastrointestinal symptoms.2,3

For patients with mild symptoms, negative tests provide reassurance and simple, symptomatic management might be all that is required (e.g. acid suppression, stool regulation). However, for those with severe symptoms that persist on therapy, ruling out life-threatening disease is not sufficient, and referral to the neurogastroenterology and motility (NGM) laboratory for physiological measurements is often indicated.

Clinical investigations aim to explain the cause of symptoms and establish a diagnosis that can guide rational treatment. Until recently, it could be argued that manometry, scintigraphy, breath tests and related tests rarely provided this information. As a result, only patients with suspected major motility disorders (e.g. achalasia, severe reflux disease or faecal incontinence) were routinely referred to the NGM laboratory for tests. Technological advances, such as high-resolution manometry (HRM), now provide objective measurements not only of motility, but also of function in terms of the movement (and digestion) of ingested material within the gastrointestinal tract. Furthermore, the ability to associate events (such as bolus retention, reflux or gas production) with symptoms provides an indication of visceral sensitivity and can identify what is causing patient complaints. Here, I discuss frequent mistakes in clinical investigation of gastrointestinal motility and function based on a series of consensus documents published by members of the International Working Group for Disorders of Gastrointestinal Motility and Function.

Yet another case of abdominal pain? 

A 41-year-old man with a recent history of weight loss, reduced appetite and nausea... 

A 41-year-old man with a recent history of weight loss, reduced appetite and nausea presents with acute abdominal pain.

On physical examination he has abdominal distension without tenderness but pain during deep palpation, Blumberg’s sign is negative and bowel sounds are sparse. The initial radiography findings are shown in figure 1 and his blood test results are shown in table 1.  Table 1 | Blood test results at presentation. Click on the picture to enlarge the table. At this stage, would you choose to give laxatives and discharge the patient, urgently perform a CT scan or endoscopy, or give a prokinetic, antibiotics, laxatives and monitor the patient every 6h? The correct decision here is to perform a CT scan, which is what the case patient underwent—the findings are shown in figure 2.  Figure 2 | Abdominal contrast-enhanced CT scan with coronal and sagittal reconstructions; images were acquired at portal venous time (about 70 seconds after injection of iodinated contrast medium).

Case Question 1

b) Crohn’s Disease
c) Intussusception
d) Megacolon

3rd EDS Surgical Skills Course (SSC)

Improve your surgical skills & register for this course on minimally invasive management of critically ill GI patients until July 1.

Alcohol Awareness Month

April is the perfect time to discuss UEG’s actions on alcoholic liver disease.

Last October, on the occasion of UEG Week 2017, we had a chance to sit and talk with Professor Helena Cortez-Pinto, a member of UEG’s Public Affairs Committee and author of the UEG Education article “Mistakes in alcoholic liver disease and how to avoid them.” Now, in the middle of Alcohol Awareness Month, we highlight the main points of our discussion and make the video of the interview available.

During our interview, Helena conveyed the importance of several aspects related to state-of-the-art treatment for patients with alcoholic liver disease (ALD), such as the necessary involvement of multidisciplinary teams to deal with both the physical and psychological sides of the disease. She also touched on the specificities of performing a liver biopsy in ALD patients, as well as some of the alcohol-related issues the UEG Public Affairs Committee is trying to get onto the EU health agenda.

The current, evident disparity between ALD research and its burden, when compared with other liver diseases, was a key point mentioned by Helena during the interview. Supporting this point is evidence from Ramon Bataller and co-authors, who developed an Attention-to-Burden Index (ABI), comparing research activities during 2010–2014 with an estimate of disease burden for the four major liver diseases, namely hepatitis B and C, ALD and nonalcoholic fatty liver disease.1 Surprisingly (or not), they found that the mean research attention for ALD was only 5%, when its overall burden was 50%, highlighting the critical need to increase awareness of ALD in the liver research community. This need was also pointed out by Helena during her interview and is something she is working to convey to Members of the European Parliament, Representatives of the European Commission and Council, as well as other EU stakeholders, as part of her work on UEG’s Public Affairs Committee, which is chaired by Markus Peck-Radosavljevic.

In a related matter, earlier this year the “Alcohol and Digestive Cancers: Time for Change” report was published by UEG EU Affairs, highlighting the alarming scale of alcohol consumption across Europe and its direct and indirect impact on digestive cancers.

More information on the work of the UEG Public Affairs Committee can be found online, along with a copy of the “Mistakes in alcoholic liver disease and how to avoid them” article from Helena and co-author Pedro Marques da Costa and other articles in the “Mistakes in…” series.

We hope you enjoy the interview! Please be sure to let us know what you think, if there are any other issues we should be considering and if there’s anyone else you would like to see us interview in future. References
  1. Ndugga N, et al. Disparities between research attention and burden in liver diseases: implications on uneven advances in pharmacological therapies in Europe and the USA. BMJ Open 2017; 7: e013620.
Further reading
  • Singal AK, et al. ACG Clinical Guideline: Alcoholic Liver Disease. Am J Gastroenterol 2018; 113: 175–194. 
  • Marcellin P and Kutala BK. Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening. Liver Int 2018; 38 (Suppl 1): 2–6.
  • Spence AD, et al. Communication of alcohol and smoking lifestyle advice to the gastroenterological patient. Best Pract Res Clin Gastroenterol 2017; 31: 597–604.
  • Campbell EJ, Lawrence AJ and Perry CJ. New steps for treating alcohol use disorder. Psychopharmacology Epub ahead of print 25 March 2018. DOI: 10.1007/s00213-018-4887-7.