Abstracts to Falk Gastro-Info 11/2019
Wang P, Berzin TM, Glissen Brown JR, Bharadwaj S, Becq A, Xiao X, Liu P, Li L, Song Y, Zhang D, Li Y, Xu G, Tu M, Liu X
Real-time automatic detection system increases colonoscopic polyp and adenoma detection rates: A prospective randomized controlled study
Objective: The effect of colonoscopy on colorectal cancer mortality is limited by several factors, among them a certain miss rate, leading to limited adenoma detection rates (ADRs). The authors investigated the effect of an automatic polyp detection system based on deep learning on polyp detection rate and ADR.
Design: In an open, non-blinded trial, consecutive patients were prospectively randomized to undergo diagnostic colonoscopy with or without assistance of a real-time automatic polyp detection system providing a simultaneous visual notice and sound alarm on polyp detection. The primary outcome was ADR.
Results: Of 1058 patients included, 536 were randomized to standard colonoscopy, and 522 were randomized to colonoscopy with computer-aided diagnosis. The artificial intelligence (AI) system significantly increased ADR (29.1% vs. 20.3%, p < 0.001) and the mean number of adenomas per patient (0.53 vs. 0.31, p < 0.001). This was due to a higher number of diminutive adenomas found (185 vs. 102, p < 0.001), while there was no statistical difference in larger adenomas (77 vs. 58, p = 0.075). In addition, the number of hyperplastic polyps was also significantly increased (114 vs. 52, p < 0.001).
Conclusions: In a low prevalent adenoma detection rate population, an automatic polyp detection system during colonoscopy resulted in a significant increase in the number of diminutive adenomas detected, as well as an increase in the rate of hyperplastic polyps. The cost-benefit ratio of such effects has to be determined further.
Dr. X. Liu, Department of Gastroenterology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, 18 Huanhua N. Rd., Qingyang, Chengdu, Sichuan, China, E-Mail: email@example.com
J Crohns Colitis. 2019;13(8):996–1002
Chavarría C, Casanova MJ, Chaparro M, Barreiro-de Acosta M, Ezquiaga E, Bujanda L, Rivero M, Argüelles-Arias F, Martín-Arranz MD, Martínez-Montiel MP, Valls M, Ferreiro-Iglesias R, Llaó J, Moraleja-Yudego I, Casellas F, Antolín-Melero B, Cortés X, Plaza R, Pineda JR, Navarro-Llavat M, García-López S, Robledo-Andrés P, Marín-Jiménez I, García-Sánchez V, Merino O, Algaba A, Arribas-López MR, Banales JM, Castro B, Castro-Laria L, Honrubia R, Almela P, Gisbert JP
Prevalence and factors associated with fatigue in patients with inflammatory bowel disease: A multicenter study
Background and aims: The aims of this study were to determine the prevalence of fatigue in patients with inflammatory bowel disease (IBD), to identify the factors associated with fatigue and its severity, to assess the impact of fatigue on quality of life, and to evaluate the relationship between fatigue and sleep disorders.
Methods: This was a prospective multicenter study conducted at 22 Spanish centers. Consecutive patients followed at IBD units were included. Fatigue was evaluated with the Fatigue Severity Scale (FSS) and the Fatigue Impact Scale (FIS). Quality of life and sleep quality were assessed using the IBD Questionnaire-Short Form (IBDQ-9) and the Pittsburgh Sleep Quality Index (PSQI), respectively.
Results: A total of 544 consecutive adult IBD patients were included (50% women, mean age 44 years, 61% Crohn's disease). The prevalence of fatigue was 41% (95% confidence interval [CI]: 37–45%). The variables associated with an increased risk of fatigue were: anxiety (odds ratio [OR] = 2.5, 95% CI: 1.6–3.7), depression (OR = 2.4, 95% CI: 1.4–3.8), presence of extraintestinal manifestations (EIMs) (OR = 1.7, 95% CI: 1.1–2.6), and treatment with systemic steroids (OR = 2.8, 95% CI: 1.4–5.7). The presence of EIMs (regression coefficient [RC] = 8.2, 95% CI: 2.3–14.2), anxiety (RC = 25.8, 95% CI: 20.0–31.5), depression (RC = 30.6, 95% CI: 24.3–37.0), and sleep disturbances (RC = 15.0, 95% CI: 9.3–20.8) were associated with severity of fatigue. Patients with fatigue had a significantly decreased IBDQ-9 score (p < 0.001).
Conclusions: The prevalence of fatigue in patients with inflammatory bowel disease is remarkably high and has a negative impact on quality of life. Therapy with systemic steroids is associated with an increased risk of fatigue. The severity of fatigue is associated with anxiety, depression, sleep disorders, and the presence of extraintestinal manifestations. Fatigue was not associated with anemia, disease activity or anti-tumor necrosis factor therapy.
Prof. Dr. J.P. Gisbert, Department of Gastroenterology, Hospital Universitario de La Princesa, Calle de Diego de León, 62, 28006 Madrid, Spain, E-Mail: firstname.lastname@example.org
Yamashina T, Uedo N, Akasaka T, Iwatsubo T, Nakatani Y, Akamatsu T, Kawamura T, Takeuchi Y, Fujii S, Kusaka T, Shimokawa T
Comparison of underwater versus conventional endoscopic mucosal resection of intermediate-size colorectal polyps
Background and aims: Endoscopic mucosal resection (EMR) with submucosal injection is an established method for removing colorectal polyps, although the en bloc resection rate decreases when polyp size exceeds 10 mm. Piecemeal resection increases local recurrence. Underwater EMR (UEMR) is an effective technique for removal of sessile colorectal polyps and the authors investigated whether it is superior to conventional EMR (CEMR).
Methods: They conducted a multicenter randomized controlled trial at 5 institutions in Japan. Patients with endoscopically diagnosed, intermediate-size (10–20 mm) sessile colorectal lesions were randomly assigned to undergo UEMR or CEMR. Only the most proximal lesion was registered. The UEMR procedure included immersion of the entire lumen in water and snare resection of the lesion without submucosal injection of normal saline. Outcomes of 108 colorectal lesions in the UEMR group and 102 lesions in the CEMR group were analyzed. R0 resection was defined as en bloc resection with a histologically confirmed negative resection margin. The primary end point was the difference in the R0 resection rates between groups.
Results: The proportions of R0 resections were 69% (95% confidence interval [CI]: 59–77%) in the UEMR group versus 50% (95% CI: 40–60%) in the CEMR group (p = 0.011). The proportions of en bloc resections were 89% (95% CI: 81–94%) in the UEMR group versus 75% (95% CI: 65–83%) in the CEMR group (p = 0.007). There was no significant difference in median procedure time (165 vs. 175 seconds) or proportions of patients with adverse events (2.8% in the UEMR group vs. 2.0% in the CEMR group).
Conclusions: In a multicenter randomized controlled trial, it was found that underwater endoscopic mucosal resection significantly increased the proportions of R0 resections for 10–20-mm sessile colorectal lesions without increasing adverse events or procedure time. Use of this procedure should be encouraged.
Prof. Dr. N. Uedo, Department of Gastrointestinal Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan, E-Mail: email@example.com
J Hepatol. 2019;71(3):586–93
Parker R, Aithal GP, Becker U, Gleeson D, Masson S, Wyatt JI, Rowe IA; WALDO study group
Natural history of histologically proven alcohol-related liver disease: A systematic review
Background and aims: To date, studies into the natural history of alcohol-related liver disease (ALD) have lacked long-term follow-up, large numbers of participants, or both. The authors performed a systematic review to summarize studies that describe the natural history of histologically proven ALD.
Methods: PubMed and Medline were searched for relevant studies according to prespecified criteria. Data were extracted to describe the prevalence of ALD, histological progression of disease and mortality. Single-proportion meta-analysis was used to combine data from studies regarding rates of progression or mortality.
Results: 37 studies were included, reporting data from 7528 participants. Amongst cohorts of hazardous drinkers, on average 15% had normal histological appearance, 27% had hepatic steatosis, 24% had steatohepatitis and 26% had cirrhosis. The annualized rates of progression of precirrhotic disease to cirrhosis were 1% (0–8%) for patients with normal histology, 3% (2–4%) for hepatic steatosis, 10% (6–17%) for steatohepatitis and 8% (3–19%) for fibrosis. Annualized mortality was 6% (4–7%) in patients with steatosis and 8% (5–13%) in cirrhosis. In patients with steatohepatitis on biopsy a marked difference was seen between inpatient cohorts (annual mortality 15%, 8–26%) and mixed cohorts of inpatients and outpatients (annual mortality 5%, 2–10%). Only in steatosis did non-liver-related mortality exceed liver-specific causes of mortality (5% per year vs. 1% per year).
Conclusions: These data confirm the observation that alcohol-related hepatic steatohepatitis requiring admission to hospital is the most dangerous subtype of alcohol-related liver disease. Alcohol-related steatosis is not a benign condition as it is associated with significant risk of mortality.
Dr. R. Parker, Leeds Liver Unit, Merville Building, St. James’s University Hospital, Beckett Street, Leeds, West Yorkshire, LS9 7TF, UK, E-Mail: firstname.lastname@example.org
van Aerts RMM, Kievit W, D'Agnolo HMA, Blijdorp CJ, Casteleijn NF, Dekker SEI, de Fijter JW, van Gastel M, Gevers TJ, van de Laarschot LFM, Lantinga MA, Losekoot M, Meijer E, Messchendorp AL, Neijenhuis MK, Pena MJ, Peters DJM, Salih M, Soonawala D, Spithoven EM, Visser FW, Wetzels JF, Zietse R, Gansevoort RT, Drenth JPH; DIPAK-1 Investigators
Lanreotide reduces liver growth in patients with autosomal dominant polycystic liver and kidney disease
Background and aims: Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). There is need for robust long-term evidence for the volume-reducing effect of somatostatin analogues. The authors made use of data from an open-label, randomized trial to determine the effects of lanreotide on height-adjusted liver volume (hTLV) and combined height-adjusted liver and kidney volume (hTLKV) in patients with ADPKD.
Methods: They performed a 120-week study comparing the renoprotective effects of lanreotide versus standard care in 305 patients with ADPKD (the DIPAK-1 study). For this analysis, the 175 patients with polycystic liver disease with hepatic cysts identified by magnetic resonance imaging and liver volume ≥ 2000 ml were studied. Of these, 93 patients were assigned to a group that received lanreotide (120 mg subcutaneously every 4 weeks) and 82 to a group that received standard care (blood pressure control, a sodium-restricted diet, and antihypertensive agents). The primary end point was percent change in hTLV between baseline and end of treatment (week 120). A secondary end point was change in hTLKV.
Results: At 120 weeks, hTLV decreased by 1.99% in the lanreotide group (95% confidence interval [CI]: -4.21–0.24) and increased by 3.92% in the control group (95% CI: 1.56–6.28). Compared with the control group, lanreotide reduced the growth of hTLV by 5.91% (95% CI: -9.18 to -2.63; p < 0.001). Growth of hTLV was still reduced by 3.87% at 4 months after the last injection of lanreotide compared with baseline (95% CI: -7.55 to -0.18; p = 0.04). Lanreotide reduced growth of hTLKV by 7.18% compared with the control group (95% CI: -10.25 to -4.12; p < 0.001).
Conclusions: In this subanalysis of a randomized trial of patients with polycystic liver disease due to autosomal dominant polycystic kidney disease, lanreotide for 120 weeks reduced the growth of liver and combined liver and kidney volume. This effect was still present 4 months after the last injection of lanreotide.
Prof. Dr. J.P.H. Drenth, Radboud University Medical Center, Department of Gastroenterology and Hepatology, Internal Postal Code 455, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands, E-Mail: email@example.com
Dig Liver Dis. 2019;51(7):993–8
Huh CW, Kim JS, Jung DH, Yang JD, Nam SW, Kwon JH, Kim BW
Optimal endoscopy timing according to the severity of underlying liver disease in patients with acute variceal bleeding
Background: Current guidelines recommend endoscopic therapy to be performed within 12 hours for acute variceal bleeding (AVB). However, the optimal timing of endoscopic therapy for AVB remains unclear.
Aims: To examine the relationship between the endoscopy timing and clinical outcomes in AVB, with emphasis on liver function and endoscopy timing.
Methods: From January 2010 to June 2017, cirrhotic patients with AVB confirmed by endoscopy were evaluated. The primary outcome was a composite of 6-week rebleeding and mortality. The authors stratified patients according to the MELD score.
Results: In 411 patients, the overall composite outcome rate was 30.9% (n = 127) at 6 weeks. Patients who underwent urgent endoscopy (≤ 12 h) had a significantly higher composite outcome than patients who underwent non-urgent endoscopy (> 12 h) (34.4% vs. 19.1%, p = 0.005). Low-risk patients who underwent urgent endoscopy were more likely to reach the composite outcome (adjusted odds ratio = 0.84/4 h, 95% confidence interval: 0.73–0.98; p = 0.027). These findings persisted even after adjustment for baseline characteristics between the urgent and non-urgent groups.
Conclusions: Urgent endoscopy is significantly associated with a poorer outcome in patients with acute variceal bleeding (AVB), especially in low-risk patients. The present result provides a treatment strategy according to the severity of underlying liver disease in patients with AVB.
Dr. J.S. Kim, Department of Internal Medicine, College of Medicine, Incheon St. Mary’s Hospital, The Catholic University of Korea, 665, Bupyeong-dong, Bupyeong-gu, Incheon 403-720, Republic of Korea, E-Mail: firstname.lastname@example.org
Schuetz P, Fehr R, Baechli V, Geiser M, Deiss M, Gomes F, Kutz A, Tribolet P, Bregenzer T, Braun N, Hoess C, Pavlicek V, Schmid S, Bilz S, Sigrist S, Brändle M, Benz C, Henzen C, Mattmann S, Thomann R, Brand C, Rutishauser J, Aujesky D, Rodondi N, Donzé J, Stanga Z, Mueller B
Individualized nutritional support in medical inpatients at nutritional risk: A randomized clinical trial
Background: Guidelines recommend the use of nutritional support during hospital stays for medical patients (patients not critically ill and not undergoing surgical procedures) at risk of malnutrition. However, the supporting evidence for this recommendation is insufficient, and there is growing concern about the possible negative effects of nutritional therapy during acute illness on recovery and clinical outcomes. The aim of the present study was thus to test the hypothesis that protocol-guided individualized nutritional support to reach protein and caloric goals reduces the risk of adverse clinical outcomes in medical inpatients at nutritional risk.
Methods: The Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT) is a pragmatic, investigator-initiated, open-label, multicenter study. The authors recruited medical patients at nutritional risk (nutritional risk screening 2002 [NRS 2002] score ≥ 3 points) and with an expected length of hospital stay of more than 4 days from 8 Swiss hospitals. These participants were randomly assigned (1:1) to receive either protocol-guided individualized nutritional support to reach protein and caloric goals (intervention group) or standard hospital food (control group). Randomization was done with variable block sizes and stratification according to study site and severity of malnutrition using an interactive web-response system. In the intervention group, individualized nutritional support goals were defined by specialist dietitians and nutritional support was initiated no later than 48 hours after admission. Patients in the control group received no dietary consultation. The composite primary end point was any adverse clinical outcome defined as all-cause mortality, admission to intensive care, non-elective hospital readmission, major complications, and decline in functional status at 30 days, and it was measured in all randomized patients who completed the trial.
Findings: 5015 patients were screened, and 2088 were recruited and monitored between April 1st, 2014, and February 28, 2018. 1050 patients were assigned to the intervention group and 1038 to the control group. 60 patients withdrew consent during the course of the trial (35 in the intervention group and 25 in the control group). During the hospital stay, caloric goals were reached in 800 (79%) and protein goals in 770 (76%) of 1015 patients in the intervention group. By 30 days, 232 (23%) patients in the intervention group experienced an adverse clinical outcome, compared with 272 (27%) of 1013 patients in the control group (adjusted odds ratio [aOR] = 0.79, 95% confidence interval [CI]: 0.64–0.97; p = 0.023). By day 30, 73 (7%) patients had died in the intervention group compared with 100 (10%) patients in the control group (aOR = 0.65, 95% CI: 0.47–0.91; p = 0.011). There was no difference in the proportion of patients who experienced side-effects from nutritional support between the intervention and the control group (162 [16%] vs. 145 [14%]; aOR = 1.16, 95% CI: 0.90–1.51; p = 0.26).
Interpretation: In medical inpatients at nutritional risk, the use of individualized nutritional support during the hospital stay improved important clinical outcomes, including survival, compared with standard hospital food. These findings strongly support the concept of systematically screening medical inpatients on hospital admission regarding nutritional risk, independent of their medical condition, followed by a nutritional assessment and introduction of individualized nutritional support in patients at risk.
Prof. Dr. P. Schuetz, Allgemeine Innere und Notfallmedizin, Kantonsspital Aarau, Tellstr., 5001 Aarau, Switzerland, E-Mail: email@example.com
Fritscher-Ravens A, Pflaum T, Mösinger M, Ruchay Z, Röcken C, Milla PJ, Das M, Böttner M, Wedel T, Schuppan D
Many patients with irritable bowel syndrome have atypical food allergies not associated with immunoglobulin E
Background and aims: Confocal laser endomicroscopy (CLE) is a technique that permits real-time detection and quantification of changes in intestinal tissues and cells, including increases in intraepithelial lymphocytes and fluid extravasation through epithelial leaks. Using CLE analysis of patients with irritable bowel syndrome (IBS), the authors found that more than half have responses to specific food components. Exclusion of the defined food led to long-term symptom relief. They used the results of CLE to detect reactions to food in a larger patient population and analyzed duodenal biopsy samples and fluid from patients to investigate mechanisms of these reactions.
Methods: In a prospective study, 155 patients with IBS received 4 challenges with each of 4 common food components via the endoscope, followed by CLE, at a tertiary medical center. Classical food allergies were excluded by negative results from immunoglobulin E serology analysis and skin tests for common food antigens. Duodenal biopsy samples and fluid were collected 2 weeks before and immediately after CLE and were analyzed by histology, immunohistochemistry, reverse transcription polymerase chain reaction, and immunoblots. Results from patients who had a response to food during CLE (CLE+) were compared with results from patients who did not have a reaction during CLE (CLE-) or healthy individuals (controls).
Results: Of the 108 patients who completed the study, 76 were CLE+ (70%), and 46 of these (61%) reacted to wheat. CLE+ patients had a 4-fold increase in prevalence of atopic disorders compared with controls (p = 0.001). Numbers of intraepithelial lymphocytes were significantly higher in duodenal biopsy samples from CLE+ versus CLE- patients or controls (p = 0.001). Expression of claudin-2 increased from crypt to villus tip (p < 0.001) and was up-regulated in CLE+ patients compared with CLE- patients or controls (p = 0.023). Levels of occludin were lower in duodenal biopsy samples from CLE+ patients versus controls (p = 0.022) and were lowest in villus tips (p < 0.001). Levels of messenger RNAs encoding inflammatory cytokines were unchanged in duodenal tissues after CLE challenge, but eosinophil degranulation increased, and levels of eosinophilic cationic protein were higher in duodenal fluid from CLE+ patients than controls (p = 0.03).
Conclusions: In a confocal laser endomicroscopy (CLE) analysis of patients with irritable bowel syndrome, it was found that more than 50% of patients could have non-classical food allergy, with immediate disruption of the intestinal barrier upon exposure to food antigens. Duodenal tissues from patients with responses to food components during CLE (CLE+)had immediate increases in expression of claudin-2 and decreases in occludin. CLE+ patients also had increased eosinophil degranulation, indicating an atypical food allergy characterized by eosinophil activation.
Prof. Dr. A. Fritscher-Ravens, Klinik für Innere Medizin I, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105 Kiel, Germany, E-Mail: firstname.lastname@example.org
Lucendo AJ, Miehlke S, Schlag C, Vieth M, von Arnim U, Molina-Infante J, Hartmann D, Bredenoord AJ, Ciriza de Los Rios C, Schubert S, Brückner S, Madisch A, Hayat J, Tack J, Attwood S, Mueller R, Greinwald R, Schoepfer A, Straumann A; International EOS-1 Study Group
Efficacy of budesonide orodispersible tablets as induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial
Background and aims: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. The authors performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE.
Methods: They performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤ 2 on a scale of 0–10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count < 5 eosinophils/high-power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily).
Results: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (p < 0.0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT versus no patients given placebo (p < 0.0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent.
Conclusions: In a randomized trial of adults with active eosinophilic esophagitis, it was found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission.
Dr. Dr. A.J. Lucendo, Department of Gastroenterology, Hospital General de Tomelloso, Vereda de Socuéllamos, s/n, 13700 Tomelloso, Ciudad Real, Spain, E-Mail: email@example.com
Am J Gastroenterol. 2019;114(7):1163–71
Lee AA, Baker JR, Wamsteker EJ, Saad R, DiMagno MJ
Small intestinal bacterial overgrowth is common in chronic pancreatitis and associates with diabetes, chronic pancreatitis severity, low zinc levels, and opiate use
Objectives: Small intestinal bacterial overgrowth (SIBO) is often present in patients with chronic pancreatitis (CP) with persistent steatorrhea, despite pancreatic enzyme replacement therapy. Overall prevalence of SIBO, diagnosed by glucose breath test (GBT), varies between 0% and 40% but 0–21% in those without upper gastrointestinal surgery. The authors investigated the prevalence and non-surgical independent predictors of SIBO in CP without upper gastrointestinal surgery.
Methods: 273 patients ≥ 18 years old had a presumptive diagnosis of CP and a GBT between 1989 and 2017. CP was defined by Mayo score (0–16) ≥ 4 and a positive GBT for SIBO by Rome consensus criteria and retrospectively collected data for 5 a priori variables (age, opiates, alcohol use, diabetes mellitus [DM], gastroparesis) and 41 investigational variables (demographics, gastrointestinal symptoms, comorbidities, CP etiologies and cofactors, CP symptom duration, Mayo score and non-diabetes components, and biochemical variables).
Results: 98 of 273 patients had definite CP and 40.8% had SIBO. Five of 46 variables predicted SIBO: opiates, p = 0.005; DM, p = 0.04; total Mayo score, p < 0.05; zinc, p = 0.005; and albumin, p < 0.05. Multivariable analysis of 3 non-correlated variables identified zinc level (odds ratio = 0.0001, p = 0.03) as the sole independent predictor of SIBO (model C-statistic = 0.89, p < 0.001).
Discussion: Small intestinal bacterial overgrowth (SIBO), diagnosed by glucose breath test, occurs in 40.8% of patients with chronic pancreatitis (CP) without upper gastrointestinal surgery. In patients with CP, markers of more severe CP (low zinc level, diabetes mellitus and increased Mayo score) and opiate use should raise clinical suspicion for SIBO, particularly in patients with persistent steatorrhea or weight loss despite pancreatic enzyme replacement therapy.
M.J. DiMagno, M.D., Associate Professor, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan School of Medicine, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA, E-Mail: firstname.lastname@example.org