Unmet needs in treatment of symptomatic uncomplicated diverticular disease and prevention of recurrent acute diverticulitis: a scoping review.

Background: Diverticular disease (DD) represents a common gastrointestinal condition that poses a heavy burden on healthcare systems worldwide. A high degree of uncertainty surrounds the therapeutic approaches for the control of symptoms in patients with symptomatic uncomplicated diverticular disease (SUDD) and primary and secondary prevention of diverticulitis and its consequences. Objectives: To review the current knowledge and discuss the unmet needs regarding the management of SUDD and the prevention of acute diverticulitis. Eligibility criteria: Randomized trials, observational studies, and systematic reviews on lifestyle/dietary interventions and medical treatment (rifaximin, mesalazine, and probiotics) of SUDD or prevention of acute diverticulitis. Sources of evidence: The literature search was performed from inception to April 2023, without language restriction, following the modified Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) reporting guidelines. References of the papers selected were checked to identify additional papers of potential interest. The final list of references was evaluated by a panel of experts, who were asked to check for any lack of relevant studies. Charting methods: Information on patient population, study design, intervention, control group, duration of the observation, and outcomes assessed was collected by two authors independently. Results: The review shows a high degree of uncertainty about therapeutic interventions, both dietary/lifestyle and pharmacological, in patients with SUDD, because of the scarcity and weakness of existing evidence. Available studies are generally of low quality, heterogeneous, and outdated, precluding the possibility to draw robust conclusions. Similarly, acute diverticulitis prevention has been seldom investigated, and there is a substantial lack of evidence supporting the role of dietary/lifestyle or pharmacological approaches to reduce the risk of diverticulitis. Conclusion: The lack of robust evidence regarding therapeutic options for gastrointestinal symptoms in SUDD patients and for primary and secondary prevention of acute diverticulitis remains an important unmet need in the management of DD.

White light computer-aided optical diagnosis of diminutive colorectal polyps in routine clinical practice.

Background and study aims Artificial Intelligence (AI) systems could make the optical diagnosis (OD) of diminutive colorectal polyps (DCPs) more reliable and objective. This study was aimed at prospectively evaluating feasibility and diagnostic performance of AI-standalone and AI-assisted OD of DCPs in a real-life setting by using a white light-based system (GI Genius, Medtronic Co, Minneapolis, Minnesota, United States). Patients and methods Consecutive colonoscopy outpatients with at least one DCP were evaluated by 11 endoscopists (5 experts and 6 non-experts in OD). DCPs were classified in real time by AI (AI-standalone OD) and by the endoscopist with the assistance of AI (AI-assisted OD), with histopathology as the reference standard. Results Of the 480 DCPs, AI provided the outcome "adenoma" or "non-adenoma" in 81.4% (95% confidence interval [CI]: 77.5-84.6). Sensitivity, specificity, positive and negative predictive value, and accuracy of AI-standalone OD were 97.0% (95% CI 94.0-98.6), 38.1% (95% CI 28.9-48.1), 80.1% (95% CI 75.2-84.2), 83.3% (95% CI 69.2-92.0), and 80.5% (95% CI 68.7-82.8%), respectively. Compared with AI-standalone, the specificity of AI-assisted OD was significantly higher (58.9%, 95% CI 49.7-67.5) and a trend toward an increase was observed for other diagnostic performance measures. Overall accuracy and negative predictive value of AI-assisted OD for experts and non-experts were 85.8% (95% CI 80.0-90.4) vs. 80.1% (95% CI 73.6-85.6) and 89.1% (95% CI 75.6-95.9) vs. 80.0% (95% CI 63.9-90.4), respectively. Conclusions Standalone AI is able to provide an OD of adenoma/non-adenoma in more than 80% of DCPs, with a high sensitivity but low specificity. The human-machine interaction improved diagnostic performance, especially when experts were involved.

GI genius endoscopy module: a clinical profile.

INTRODUCTION: The identification of early-stage colorectal cancers (CRC) and the resection of pre-cancerous neoplastic lesions through colonoscopy allows to decrease both CRC incidence and mortality. However, colonoscopy miss rates up to 26% for adenomas and 9% for advanced adenomas have been reported. In recent years, artificial intelligence (AI) systems have been emerging as easy-to-use tools, potentially lowering the risk of missing lesions. AREAS COVERED: This review paper focuses on GI Genius device (Medtronic Co. Minneapolis, MN, U.S.A.) a computer-assisted tool designed to assist endoscopists during standard white-light colonoscopies in detecting mucosal lesions. EXPERT OPINION: Randomized controlled trials (RCTs) suggest that GI Genius is a safe and effective tool for improving adenoma detection, especially in CRC screening and surveillance colonoscopies. However, its impact seems to be less significant among experienced endoscopists and in real-world clinical scenarios compared to the controlled conditions of RCTs. Furthermore, it appears that GI Genius mainly enhances the detection of non-advanced, small polyps, but does not significantly impact the identification of advanced and difficult-to-detect adenoma. When using GI Genius, no complications were documented. Only a small number of studies reported an increased in withdrawal time or the removal of non-neoplastic lesions.

SIED-GISCOR recommendations for colonoscopy in screening programs: Part I - Diagnostic.

The implementation of FIT programs reduces incidence and mortality from CRC in the screened subjects. The ultimate efficacy for CRC morbidity and mortality prevention in a FIT program depends on the colonoscopy in FIT+ subjects that has the task of detecting and removing these advanced lesions. Recently, there has been growing evidence on factors that influence the quality of colonoscopy specifically withing organized FIT programs, prompting to dedicated interventions in order to maximize the benefit/harm ratio of post-FIT colonoscopy. This document focuses on the diagnostic phase of colonoscopy, providing indications on how to standardise colonoscopy in FIT+ subjects, regarding timing of examination, management of antithrombotic therapy, bowel preparation, competence and sedation.

Scoring systems for risk stratification in upper and lower gastrointestinal bleeding.

Several scoring systems have been developed for both upper and lower GI bleeding to predict the bleeding severity and discriminate between low-risk patients, who may be suitable for outpatient management, and those who would likely need hospital-based interventions and are at high risk for adverse outcomes. Risk scores created to identify low-risk patients (namely the Glasgow Blatchford Score and the Oakland score) showed very good discriminative performances and their implementation has proven to be effective in reducing hospital admissions and healthcare burden. Conversely, the performances of risk scores in identifying specific adverse events to define high-risk patients are less accurate, and whether their integration into routine clinical practice has a tangible impact on patient management remains unproven. This review describes the existing risk score systems for GI bleeding, emphasizes key research findings, elucidates the circumstances in which their utilization can be beneficial, examines their constraints when considering routine clinical application, and discuss future development.

Prevalence of Disease-Related Malnutrition and Micronutrients Deficit in Patients with Inflammatory Bowel Disease: A Multicentric Cross-Sectional Study by the GSMII (Inflammatory Bowel Disease Study Group).

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) patients might experience disease-related malnutrition (DRM), but prevalence and risk factors are not well defined. The primary aim of the study was to define the prevalence of DRM and micronutrient deficiency in IBD patients; the secondary aim was to assess variables related to DRM. MATERIALS AND METHODS: A multicenter, cross-sectional study was performed including consecutive adult IBD patients during a period of 2 weeks. Nutritional status was assessed with the body mass index (BMI) and the Malnutrition Universal Screening Tool. DRM was defined according to European Society for Clinical Nutrition and Metabolism guidelines. RESULTS: Among the 295 enrolled patients, the prevalence of DRM was 23%, with no statistical difference between Crohn's disease and ulcerative colitis. Compared with well-nourished patients, patients with DRM showed higher rate of hospitalization in the previous month, were more often receiving systemic steroids, and had lower hemoglobin, albumin, and prealbumin levels and higher median C-reactive protein levels. At univariate logistic regression, current hospitalization, hospitalization in the previous month, low serum albumin, low BMI, high C-reactive protein, high Crohn's Disease Activity Index, and female sex were variables related to DRM. At the multivariate logistic regression, low BMI, current hospitalization and hospitalization in the previous month were significantly associated with DRM. In 23% of IBD patients, a deficiency of at least 1 micronutrient was observed, with no difference between ulcerative colitis and Crohn's disease. CONCLUSIONS: DRM and microelements malnutrition are frequent conditions in the IBD population. DRM seems to be associated with disease activity and hospitalization.

Combination of Mucosa-Exposure Device and Computer-Aided Detection for Adenoma Detection During Colonoscopy: A Randomized Trial.

BACKGROUND & AIMS: Both computer-aided detection (CADe)-assisted and Endocuff-assisted colonoscopy have been found to increase adenoma detection. We investigated the performance of the combination of the 2 tools compared with CADe-assisted colonoscopy alone to detect colorectal neoplasias during colonoscopy in a multicenter randomized trial. METHODS: Men and women undergoing colonoscopy for colorectal cancer screening, polyp surveillance, or clincial indications at 6 centers in Italy and Switzerland were enrolled. Patients were assigned (1:1) to colonoscopy with the combinations of CADe (GI-Genius; Medtronic) and a mucosal exposure device (Endocuff Vision [ECV]; Olympus) or to CADe-assisted colonoscopy alone (control group). All detected lesions were removed and sent to histopathology for diagnosis. The primary outcome was adenoma detection rate (percentage of patients with at least 1 histologically proven adenoma or carcinoma). Secondary outcomes were adenomas detected per colonoscopy, advanced adenomas and serrated lesions detection rate, the rate of unnecessary polypectomies (polyp resection without histologically proven adenomas), and withdrawal time. RESULTS: From July 1, 2021 to May 31, 2022, there were 1316 subjects randomized and eligible for analysis; 660 to the ECV group, 656 to the control group). The adenoma detection rate was significantly higher in the ECV group (49.6%) than in the control group (44.0%) (relative risk, 1.12; 95% CI, 1.00-1.26; P = .04). Adenomas detected per colonoscopy were significantly higher in the ECV group (mean ± SD, 0.94 ± 0.54) than in the control group (0.74 ± 0.21) (incidence rate ratio, 1.26; 95% CI, 1.04-1.54; P = .02). The 2 groups did not differ in term of detection of advanced adenomas and serrated lesions. There was no significant difference between groups in mean ± SD withdrawal time (9.01 ± 2.48 seconds for the ECV group vs 8.96 ± 2.24 seconds for controls; P = .69) or proportion of subjects undergoing unnecessary polypectomies (relative risk, 0.89; 95% CI, 0.69-1.14; P = .38). CONCLUSIONS: The combination of CADe and ECV during colonoscopy increases adenoma detection rate and adenomas detected per colonoscopy without increasing withdrawal time compared with CADe alone. CLINICALTRIALS: gov, Number: NCT04676308.

Factors influencing the presence of potentially explosive gases during colonoscopy: Results of the SATISFACTION study.

This study tested the hypothesis that bowel preparation with mannitol should not affect the colonic concentration of H2 and CH4 . Therefore, the SATISFACTION study, an international, multicenter, randomized, parallel-group phase II-III study investigated this issue. The phase II dose-finding part of the study evaluated H2 , CH4 , and O2 concentrations in 179 patients randomized to treatment with 50 g, 100 g, or 150 g mannitol. Phase III of the study compared the presence of intestinal gases in 680 patients randomized (1:1) to receive mannitol 100 g in single dose or a standard split-dose 2 L polyethylene glycol (PEG)-Asc preparation (2 L PEG-Asc). Phase II results showed that mannitol did not influence the concentration of intestinal gases. During phase III, no patient in either group had H2 or CH4 concentrations above the critical thresholds. In patients with H2 and/or CH4 levels above detectable concentrations, the mean values were below the risk thresholds by at least one order of magnitude. The results also highlighted the effectiveness of standard washing and insufflation maneuvers in removing residual intestinal gases. In conclusion, bowel cleansing with mannitol was safe as the concentrations of H2 and CH4 were the same as those found in patients prepared with 2 L PEG-Asc. In both groups, the concentrations of gases were influenced more by the degree of cleansing achieved and the insufflation and washing maneuvers performed than by the preparation used for bowel cleansing. The trial protocol was registered with ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT04759885) and with EudraCT (eudract_number: 2019-002856-18).

Artificial intelligence-assisted optical diagnosis for the resect-and-discard strategy in clinical practice: the Artificial intelligence BLI Characterization (ABC) study.

BACKGROUND: Optical diagnosis of colonic polyps is poorly reproducible outside of high volume referral centers. The present study aimed to assess whether real-time artificial intelligence (AI)-assisted optical diagnosis is accurate enough to implement the leave-in-situ strategy for diminutive (≤ 5 mm) rectosigmoid polyps (DRSPs). METHODS: Consecutive colonoscopy outpatients with ≥ 1 DRSP were included. DRSPs were categorized as adenomas or nonadenomas by the endoscopists, who had differing expertise in optical diagnosis, with the assistance of a real-time AI system (CAD-EYE). The primary end point was ≥ 90 % negative predictive value (NPV) for adenomatous histology in high confidence AI-assisted optical diagnosis of DRSPs (Preservation and Incorporation of Valuable endoscopic Innovations [PIVI-1] threshold), with histopathology as the reference standard. The agreement between optical- and histology-based post-polypectomy surveillance intervals (≥ 90 %; PIVI-2 threshold) was also calculated according to European Society of Gastrointestinal Endoscopy (ESGE) and United States Multi-Society Task Force (USMSTF) guidelines. RESULTS: Overall 596 DRSPs were retrieved for histology in 389 patients; an AI-assisted high confidence optical diagnosis was made in 92.3 %. The NPV of AI-assisted optical diagnosis for DRSPs (PIVI-1) was 91.0 % (95 %CI 87.1 %-93.9 %). The PIVI-2 threshold was met with 97.4 % (95 %CI 95.7 %-98.9 %) and 92.6 % (95 %CI 90.0 %-95.2 %) of patients according to ESGE and USMSTF, respectively. AI-assisted optical diagnosis accuracy was significantly lower for nonexperts (82.3 %, 95 %CI 76.4 %-87.3 %) than for experts (91.9 %, 95 %CI 88.5 %-94.5 %); however, nonexperts quickly approached the performance levels of experts over time. CONCLUSION: AI-assisted optical diagnosis matches the required PIVI thresholds. This does not however offset the need for endoscopists' high level confidence and expertise. The AI system seems to be useful, especially for nonexperts.

An Italian prospective multicenter study on colonoscopy practice and quality: What has changed in the last 10 years.

BACKGROUND: A relevant number of adenomas can be missed during colonoscopy. AIMS: Assess the current status of colonoscopy procedures in Italian centers. METHODS: A prospective observational study involving 17 hospitals (34 endoscopists) included consecutive patients undergoing standard colonoscopy. In the first phase, endoscopists performed consecutive colonoscopies. In the second phase, retraining via an online learning platform was planned, while in the third phase data were collected analogously to phase 1. RESULTS: A total of 3,504 patients were enrolled. Overall, a BBPS score ≥6 was obtained in 95.6% of cases (94.8% and 96.9% in the pre- and post-training phases, respectively). 88.4% of colonoscopies had a withdrawal time ≥6 min (88.2% and 88.7% in the pre- and post-training phases). Median adenoma detection rate (ADR) was 39.1%, with no significant differences between the pre- and post-training phases (40.1% vs 36.9%; P = 0.83). In total, 81% of endoscopists had a ADR performance above the 25% threshold. CONCLUSION: High colonoscopy quality standards are achieved by the Italian hospitals involved. Quality improvement initiatives and repeated module-based colonoscopy-training have been promoted in Italy during the last decade, which appear to have had a significant impact on quality colonoscopy metrics together with the activation of colorectal cancer screening programs.

Clinical value of alarm features for colorectal cancer: a meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is a common neoplasm in Western countries. Prioritizing access to colonoscopy appears of critical relevance. Alarm features are considered to increase the likelihood of CRC. Our aim was to assess the diagnostic performance of alarm features for CRC diagnosis. METHODS: We performed a systematic review and meta-analysis of studies reporting the diagnostic accuracy of alarm features (rectal bleeding, anemia, change in bowel habit, and weight loss) for CRC, published up to September 2021. Colonoscopy was required as the reference diagnostic test. Diagnostic accuracy measures were pooled by a bivariate mixed-effects regression model. The number needed to scope (NNS; i. e. the number of patients who need to undergo colonoscopy to diagnose one CRC) according to each alarm feature was calculated. RESULTS: 31 studies with 45 100 patients (mean age 31-88 years; men 36 %-63 %) were included. The prevalence of CRC ranged from 0.2 % to 22 %. Sensitivity was suboptimal, ranging from 12.4 % for weight loss to 49 % for rectal bleeding, whereas specificity ranged from 69.8 % for rectal bleeding to 91.9 % for weight loss. Taken individually, rectal bleeding and anemia would be the only practical alarm features mandating colonoscopy (NNS 5.3 and 6.7, respectively). CONCLUSIONS: When considered independently, alarm features have variable accuracy for CRC, given the high heterogeneity of study populations reflected by wide variability in CRC prevalence. Rectal bleeding and anemia are the most practical to select patients for colonoscopy. Integration of alarm features in a comprehensive evaluation of patients should be considered.

Oral mannitol for bowel preparation: a dose-finding phase II study.

BACKGROUND: Successful bowel preparation (BP) for colonoscopy depends on the instructions, diet, the laxative product, and patient adherence, which all affect colonoscopy quality. Nevertheless, there are no laxatives which combine effectiveness, safety, easy self-administration, good patient acceptance, and low cost. However, mannitol, a sugar alcohol, could be an attractive candidate for use in clinical practice if it is shown to demonstrate adequate efficacy and safety. AIMS: The present phase II dose-finding study compared three doses of mannitol (50, 100, and 150 g) to identify the best dose to be used in a subsequent phase III study. METHODS: The Boston Bowel Preparation Scale, caecal intubation rate, adherence, acceptability, and safety profile, including measurement of potentially dangerous colonic gas concentrations (CH4, H2, O2), were considered in all patients. A weighted algorithm was used to identify the best mannitol dose for use in the subsequent study. RESULTS: The per-protocol population included 60 patients in the 50 g group, 54 in the 100 g group, and 49 in the 150 g group. The 100 g dose was the best as it afforded optimal colon cleansing efficacy (94.4% of patients had adequate BP), adherence, acceptability, and safety, including negligible gas concentrations. CONCLUSIONS: The present study demonstrated that the colon cleansing efficacy and safety of mannitol were dose dependent. Conversely, gas concentrations were not dose dependent and negligible in all patients. Combined evaluation of efficacy, tolerability, and safety, using a weighted algorithm, determined that mannitol 100 g was the best dose for the phase III study.

Incidence, risk and protective factors of symptoms after colonoscopy.

BACKGROUND: Few studies focused on minor adverse events which may develop after colonoscopy. AIMS: To investigate the incidence and factors associated to post-colonoscopy symptoms. METHODS: This is a prospective study conducted in 10 Italian hospitals. The main outcome was a cumulative score combining 10 gastrointestinal (GI) symptoms occurring the week following colonoscopy. The analyses were conducted via multivariate logistic regression. RESULTS: Of 793 subjects included in the analysis, 361 (45.5%) complained the new onset of at least one GI symptom after the exam; one symptom was reported by 202 (25.5%), two or more symptoms by 159 (20.1%). Newly developed symptoms more frequently reported were epigastric/abdominal bloating (32.2%), pain (17.3%), and dyspeptic symptoms (17.9%). Symptoms were associated with female sex (odds ratio [OR]=2.54), increasing number of symptoms developed during bowel preparation intake (OR=1.35) and somatic symptoms (OR=1.27). An inverse association was observed with better mood (OR=0.74). A high-risk profile was identified, represented by women with bad mood and somatic symptoms (OR=8.81). CONCLUSION: About half of the patients develop de novo GI symptoms following colonoscopy. Improving bowel preparation tolerability may reduce the incidence of post-colonoscopy symptoms, especially in more vulnerable patients.

Determinants of symptom burden related to bowel preparation for colonoscopy.

BACKGROUND: Symptoms developing during bowel preparation are major concerns among subjects who refuse the procedure. AIMS: We aimed to explore the determinants of symptoms occurring during preparation among patients undergoing elective colonoscopy. METHODS: This is a prospective multicenter study conducted in 10 Italian hospitals. A multidimensional approach collecting socio-demographic, clinical, psychological and occupational information before colonoscopy through validated instruments was used. Outcome was a four-category cumulative score based on symptoms occurring during preparation, according to the Mayo Clinic Bowel Prep Tolerability Questionnaire, weighted by intensity. Missing values were addressed through multiple imputation. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through multivariate logistic regression models. RESULTS: 1137 subjects were enrolled. Severe symptoms were associated with female sex (OR=3.64, 95%CI 1.94-6.83), heavier working hours (OR=1.13, 95% CI=1.01-1.25), previous gastrointestinal symptoms (OR=7.81, 95% CI 2.36-25.8 for high score), somatic symptoms (OR=2.19, 95% CI=1.06-4.49 for multiple symptoms), day-before regimen (OR=2.71, 95%CI 1.28-5.73). On the other hand, age ≥60 years (OR=0.10, 95% CI 0.02-0.44) and good mood (p=0.042) were protective factors. A high-risk profile was identified, including women with low mood and somatic symptoms (OR=15.5, 95%CI 4.56-52.7). CONCLUSIONS: We identified previously unreported determinants of symptoms burdening bowel preparation and identified a particularly vulnerable phenotype. Symptoms during preparation especially impact heavier working activity.

Pathophysiology and therapeutic management of anemia in gastrointestinal disorders.

INTRODUCTION: Anemia is a common complication of gastrointestinal (GI) disorders, with a prevalence up to 60% in celiac disease (CeD) and inflammatory bowel disease (IBD). Iron deficiency anemia (IDA) is the most prevalent form of anemia in these conditions, but chronic inflammation and vitamin B12 deficiency represent other common contributing mechanisms, especially in IBD. AREAS COVERED: We discuss the pathogenesis of anemia in various medical GI disorders, the sometime problematic distinction between IDA, anemia of inflammation (AI) and the association of the two, and therapeutic and preventive measures that can be useful for the management of anemia in GI disorders. Unfortunately, with the exception of IDA and AI in IBD, large RCT concerning the treatment of anemia in GI disorders are lacking. EXPERT OPINION: Anemia management strategies in GI disorders are outlined, with a focus on the main prevention, diagnostic, and therapeutic measures. Specific problems and situations such as the role of gluten-free diet for IDA treatment in CeD, the choice between oral and parenteral supplementation of iron or vitamin B12 in carential anemias, the use of endoscopic procedures to stop bleeding in intestinal angiodysplasia and preventive/treatment strategies for NSAID-associated GI bleeding are discussed.

Efficacy of a computer-aided detection system in a fecal immunochemical test-based organized colorectal cancer screening program: a randomized controlled trial (AIFIT study).

BACKGROUND: Computer-aided detection (CADe) increases adenoma detection in primary screening colonoscopy. The potential benefit of CADe in a fecal immunochemical test (FIT)-based colorectal cancer (CRC) screening program is unknown. This study assessed whether use of CADe increases the adenoma detection rate (ADR) in a FIT-based CRC screening program. METHODS: In a multicenter, randomized trial, FIT-positive individuals aged 50-74 years undergoing colonoscopy, were randomized (1:1) to receive high definition white-light (HDWL) colonoscopy, with or without a real-time deep-learning CADe by endoscopists with baseline ADR > 25 %. The primary outcome was ADR. Secondary outcomes were mean number of adenomas per colonoscopy (APC) and advanced adenoma detection rate (advanced-ADR). Subgroup analysis according to baseline endoscopists' ADR (≤ 40 %, 41 %-45 %, ≥ 46 %) was also performed. RESULTS: 800 individuals (median age 61.0 years [interquartile range 55-67]; 409 men) were included: 405 underwent CADe-assisted colonoscopy and 395 underwent HDWL colonoscopy alone. ADR and APC were significantly higher in the CADe group than in the HDWL arm: ADR 53.6 % (95 %CI 48.6 %-58.5 %) vs. 45.3 % (95 %CI 40.3 %-50.45 %; RR 1.18; 95 %CI 1.03-1.36); APC 1.13 (SD 1.54) vs. 0.90 (SD 1.32; P  = 0.03). No significant difference in advanced-ADR was found (18.5 % [95 %CI 14.8 %-22.6 %] vs. 15.9 % [95 %CI 12.5 %-19.9 %], respectively). An increase in ADR was observed in all endoscopist groups regardless of baseline ADR. CONCLUSIONS: Incorporating CADe significantly increased ADR and APC in the framework of a FIT-based CRC screening program. The impact of CADe appeared to be consistent regardless of endoscopist baseline ADR.