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1.  Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis 
Alimentary pharmacology & therapeutics  2013;38(2):10.1111/apt.12352.
SUMMARY
Background
Non-alcoholic steatohepatitis (NASH) is a common cause of serum alanine aminotransferase (ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations reflect the liver injury.
Aim
To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy.
Methods
The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non-alcoholic Steatohepatitis (PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to ≤40 U/L and by ≥30% of baseline. Liver biopsies taken before and after treatment were scored for non-alcoholic fatty liver disease activity (NAS) and fibrosis.
Results
ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients (P < 0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS (P < 0.001), but not fibrosis scores (P = 0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both (P < 0.05). Weight loss (≥2 kg) was also associated with ALT response (P < 0.001), improvements in NAS (P < 0.001) and fibrosis (P < 0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (≥2 kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E.
Conclusions
Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. Clinical Trial Number: NCT00063622.
doi:10.1111/apt.12352
PMCID: PMC3775262  PMID: 23718573
2.  Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis 
Alimentary pharmacology & therapeutics  2014;39(11):1276-1285.
SUMMARY
Background
Gut microbiota modifiers may have beneficial effects of non-alcoholic fatty liver disease (NAFLD) but randomised controlled trials (RCT) are lacking in children.
Aim
We performed a double-blind RCT of VSL#3 vs. placebo in obese children with biopsy-proven NAFLD.
Methods
Of 48 randomised children, 44 (22 VSL#3 and 22 placebo) completed the study. The main outcome was the change in fatty liver severity at 4 months as detected by ultrasonography. Secondary outcomes were the changes in triglycerides, insulin resistance as detected by the homoeostasis model assessment (HOMA), alanine transaminase (ALT), body mass index (BMI), glucagon-like peptide 1 (GLP-1) and activated GLP-1 (aGLP-1). Ordinal and linear models with cluster confidence intervals were used to evaluate the efficacy of VSL#3 vs. placebo at 4 months.
Results
At baseline, moderate and severe NAFLD were present in 64% and 36% of PLA children and in 55% and 45% of VSL#3 children. The probability that children supplemented with VSL#3 had none, light, moderate or severe FL at the end of the study was 21%, 70%, 9% and 0% respectively with corresponding values of 0%, 7%, 76% and 17% for the placebo group (P < 0.001). No between-group differences were detected in triglycerides, HOMA and ALT while BMI decreased and GLP-1 and aGLP1 increased in the VSL#3 group (P < 0.001 for all comparisons).
Conclusions
A 4-month supplement of VSL#3 significantly improves NAFLD in children. The VSL#3-dependent GLP-1 increase could be responsible for these beneficial effects. Trial identifier: NCT01650025 (www.clinicaltrial.gov)
doi:10.1111/apt.12758
PMCID: PMC4046270  PMID: 24738701
3.  A new method for determining gastric acid output using a wireless ph sensing capsule 
Alimentary pharmacology & therapeutics  2013;37(12):1198-1209.
BACKGROUND
Gastroesophageal reflux disease (GERD) and gastric acid hypersecretion respond well to suppression of gastric acid secretion. However, clinical management and research in diseases of acid secretion have been hindered by the lack of a non-invasive, accurate and reproducible tool to measure gastric acid output (GAO). Thus, symptoms or, in refractory cases, invasive testing may guide acid suppression therapy.
AIM
To present and validate a novel, non-invasive method of GAO analysis in healthy subjects using a wireless pH sensor, SmartPill® (SP) (SmartPill® Corporation, Buffalo, NY).
METHODS
Twenty healthy subjects underwent conventional GAO studies with a nasogastric tube. Variables impacting liquid meal-stimulated GAO analysis were assessed by modeling and in vitro verification. Buffering capacity of Ensure Plus® was empirically determined. SP GAO was calculated using the rate of acidification of the Ensure Plus® meal. Gastric emptying scintigraphy and GAO studies with radiolabeled Ensure Plus® and SP assessed emptying time, acidification rate and mixing. Twelve subjects had a second SP GAO study to assess reproducibility.
RESULTS
Meal stimulated SP GAO analysis was dependent on acid secretion rate and meal buffering capacity but not on gastric emptying time. On repeated studies, SP GAO strongly correlated with conventional BAO (r=0.51, P=0.02), MAO (r=0.72, P=0.0004) and PAO; (r=0.60, P=0.006). The SP sampled the stomach well during meal acidification.
CONCLUSIONS
SP GAO analysis is a non-invasive, accurate and reproducible method for the quantitative measurement of GAO in healthy subjects. SP GAO analysis could facilitate research and clinical management of GERD and other disorders of gastric acid secretion.
doi:10.1111/apt.12325
PMCID: PMC3703786  PMID: 23639004
acid output; wireless capsule; SmartPill®; gastroesophageal reflux disease
4.  Dysmotility and ppi use are independent risk factors for small intestinal bacterial and/or fungal overgrowth 
Alimentary pharmacology & therapeutics  2013;37(11):1103-1111.
Introduction
Whether intestinal dysmotility and proton pump inhibitor (PPI) use either independently or together contributes to small intestinal bacterial overgrowth (SIBO), and/or small intestinal fungal overgrowth (SIFO) is not known.
Aim
Investigate the role of dysmotility and PPI use in patients with persistent gastrointestinal complaints.
Methods
Patients with unexplained gastrointestinal symptoms and negative endoscopy/radiology tests completed a validated symptom questionnaire and underwent 24-hour ambulatory antro-duodeno-jejunal manometry (ADJM). Simultaneously, duodenal aspirate was obtained for aerobic, anaerobic and fungal culture. Dysmotility was diagnosed by (> 2): absent phase III MMC, absent/diminished postprandial response, diminished amplitude of antral/intestinal phasic activity, impaired antro-duodenal coordination. Bacterial growth ≥103 CFU/mL or fungal growth was considered evidence for SIBO/SIFO. PPI use was documented. Correlation of symptoms with presence of SIBO or SIFO were assessed.
Results
150 subjects (M/F=47/103) were evaluated; 94/150 (63%) had overgrowth: 38/94 (40%) had SIBO, 24/94 (26%) had SIFO, and 32/94 (34%) had mixed SIBO/SIFO. SIBO was predominately due to Streptococcus, Enterococcus, Klebsiella, and E. coli. SIFO was due to Candida. 80/150 (53%) patients had dysmotility and 65/150 (43%) used PPI. PPI use (p=.0063) and Dysmotility (p=.0003) were independent significant risk factors (p<0.05) for overgrowth, but together did not pose additional risk. Symptom profiles were similar between those with or without SIBO/SIFO.
Conclusions
Dysmotility and PPI use were independent risk factors for SIBO or SIFO and were present in over 50% of subjects with unexplained gastrointestinal symptoms. Diagnosis of overgrowth requires testing because symptoms were poor predictors of overgrowth.
doi:10.1111/apt.12304
PMCID: PMC3764612  PMID: 23574267
Dysmotility; proton pump inhibitor; Small Intestinal Bacterial Overgrowth; Small Intestinal Fungal Overgrowth; breath testing; antroduodenojejunal manometry
5.  Genetic variation in the beta-2 adrenergic receptor (ADRB2) predicts functional gastrointestinal diagnoses and poorer health-related quality of life 
SUMMARY
Background
The beta-2 adrenergic receptor (ADRB2) is an important target for epinephrine, a neurotransmitter in pain signalling. ADRB2 haplotypes affect receptor expression and ligand response, and have been linked to painful non-GI disorders.
Aims
To assess whether ADRB2 polymorphisms (rs1042713, rs1042714) are risk alleles for functional GI (FGID) and extraintestinal functional (EIFD) diagnoses, and whether ADRB2 predicts GI symptoms and health-related quality of life (HRQOL).
Methods
Of 398 subjects (49.6 ± 2.9 years, 68.0% female), 170 (42.5%) met Rome III criteria for ≥1 FGID [IBS (n = 139, 34.9%); functional dyspepsia (FD, n = 136, 34.1%), functional chest pain (FCP, n = 25, 6.2%)], while 228 were healthy controls. FGID subjects reported on bowel symptom severity and burden (10-cm VAS), frequency (days/last 2 weeks), EIFD, psychiatric diagnoses and HRQOL (SF 36). Multivariable models determined the contribution of ADRB2 polymorphisms to HRQOL, and mediational analyses assessed functional diagnoses as potential intermediates.
Results
rs1042714 minor G alleles were associated with FGID diagnoses (OR 1.8; 95% CI 1.2–2.7; P = 0.009), particularly FD (OR 2.1, 95% CI 1.3–3.3), with trends towards IBS (P = 0.19) and FCP (P = 0.06) diagnoses. Within IBS, G allele carriers had more severe bowel symptoms (P = 0.025), and symptomatic days (P = 0.009). G allele carriers had greater numbers of EIFD (1.0 ± 0.1 vs. 0.4 ± 0.07, P < 0.001) and poorer HRQOL. The effect of ADRB2 on HRQOL was partially mediated by FGID, EIFD and psychiatric diagnoses.
Conclusions
ADRB2 minor alleles at rs1042714 predict FGID and EIFD, and may influence bowel symptom severity and HRQOL. These findings provide indirect evidence of sympathetic nervous system role in FGID pathophysiology.
doi:10.1111/apt.12378
PMCID: PMC4017784  PMID: 23786226
6.  Long Term Outcome of Chronic Hepatitis C after Sustained Virological Response to Interferon-Based Therapy 
Background
While the short-term benefits of a sustained virological response (SVR) to interferon-based therapies of chronic hepatitis C (CHC) are well known, the long-term consequences of SVR are less clear.
Aims
To assess changes in markers of disease activity and fibrosis in patients followed up to 23 years post-SVR.
Methods
The first 103 SVR patients (from 1984 to 2003) at the National Institutes of Health Clinical Center were evaluated. Serum markers before treatment and at the last visit were compared. Evaluations after 2007 included transient elastography (TE).
Results
Of 103 patients, 3 subsequently relapsed 0.7, 6.3 and 6.5 years post-therapy. The remaining 100 patients (56 men, mean age 56 years) maintained SVR at final follow-up. No patients developed hepatic decompensation, but one with pre-treatment cirrhosis died 12 years post-SVR of hepatocellular carcinoma. In comparison to pre-treatment values, markers improved at follow-up, including mean ALT (152 to 27U/L), AST (87 to 24U/L), alkaline phosphatase (78 to 69U/L), IgG (1463 to 1113mg/dL), platelet count (209,000 to 239,000/μL) and AST to platelet count ratio index (APRI:1.31 to 0.33). TE was performed in 69 patients and was normal (<7.0 KPa) in 60%, moderately elevated (7.1–13.8) in 31% and cirrhotic range (>13.8) in 9%. TE and platelet counts at follow-up correlated with fibrosis on pre-treatment liver biopsy (p<0.001).
Conclusions
In 97% of patients with CHC, SVR is durable without evidence of disease progression, although some degree of hepatic fibrosis may persist and patients with pre-treatment cirrhosis are at continuing low risk for hepatocellular carcinoma.
doi:10.1111/apt.12273
PMCID: PMC3627475  PMID: 23461575
hepatitis C; antiviral therapy; natural history; cirrhosis; hepatocellular carcinoma; noninvasive markers of fibrosis; transient elastography
7.  Weekend Hospitalizations and Post-operative Complications following urgent surgery for Ulcerative Colitis and Crohn’s Disease 
Background
There is increasing complexity in the management of patients with acute severe exacerbation of inflammatory bowel disease (IBD; Crohn’s disease (CD), ulcerative colitis (UC)) with frequent requirement for urgent surgery.
Aim
To determine whether a weekend effect exists for IBD care in the United States.
Methods
We used data from the Nationwide Inpatient Sample (NIS) 2007, the largest all-payer hospitalization database in the United States. Discharges with a diagnosis of CD or UC who underwent urgent intestinal surgery within 2 days of hospitalization were identified using the appropriate ICD-9 codes. The independent effect of admission on a weekend was examined using multivariate logistic regression adjusting for potential confounders.
Results
Our study included 7,112 urgent intestinal surgeries in IBD patients, 21% of which occurred following weekend admissions. There was no difference in disease severity between weekend and weekday admissions. Post-operative complications were more common following weekend than weekday hospitalizations in UC (odds ratio (OR) 1.71, 95% confidence interval (CI) 1.01–2.90). The most common post-operative complication was post-operative infections (Weekend 30% vs. weekday 20%, p=0.04). The most striking difference between weekend and weekday hospitalizations was for need for repeat laparotomy (OR 11.5), mechanical wound complications (OR 10.03) and pulmonary complications (OR 2.22). In contrast, occurrence of any post-operative complication in CD was similar between weekday and weekend admissions.
Conclusion
Patients with UC hospitalized on a weekend undergoing urgent surgery within 2 days have an increased risk for post-operative complications, in particular mechanical wound complications, need for repeat laparotomy, and post-operative infections.
doi:10.1111/apt.12272
PMCID: PMC3618593  PMID: 23451882
weekend effect; post-operative complications; Crohn’s disease; ulcerative colitis
8.  Myelosuppression monitoring after immunomodulator initiation in veterans with inflammatory bowel disease: a national practice audit 
SUMMARY
Background
Immunomodulator medications (IMM) play a vital role in the care of patients with inflammatory bowel disease (IBD). IBD practice guidelines recommend myelosuppression monitoring after initiation of IMM.
Aim
To identify adherence rates and predictors of myelosuppression monitoring after IMM initiation in a large practice setting.
Methods
We identified a national cohort of VA users with IBD for the fiscal years 2003–2009 using the Veterans Affairs administrative datasets. Subjects with filled prescriptions for IMM were included. The primary endpoint was the proportion of subjects who had a white blood cell (WBC) test completed within 90 days of the IMM index date. Determinants of myelosuppression monitoring were identified by univariate and multivariate analyses.
Results
A total of 6045 unique IBD patients were identified with filled IMM prescriptions. Overall, only 57% of subjects completed a WBC test within 90 days of IMM index date. Monitoring rates increased over time, from 48% in 2003 to 75% in 2009. There was variability of monitoring rates by facility, ranging from 0 to 83%. In multivariate analyses, older age at IMM index date was associated with a lower rate of monitoring. Frequency of VA encounters and IMM index date were associated with increased rates of myelosuppression monitoring.
Conclusions
Monitoring for myelosuppression among veterans with inflammatory bowel disease after immunomodulator medications initiation is low with wide variability based on facility. This may reflect a low quality of care among veterans with IBD. Provider- and system-wide interventions are needed to improve adherence and reduce variability of immunomodulator medications monitoring across facilities.
doi:10.1111/apt.12075
PMCID: PMC3998909  PMID: 23061548
9.  PROMIS computerised adaptive tests are dynamic instruments to measure health-related quality of life in patients with cirrhosis 
Summary
Background
Cirrhotic patients have an impaired health-related quality of life (HRQOL), which is usually analysed using static paper-pencil questionnaires. The Patient Reported Outcomes Measurement Information System (PROMIS) computerised adaptive testing (CAT) are flexible, freely available, noncopyrighted, HRQOL instruments with US-based norms across 11 domains. CAT presents five to seven questions/domain depending on the patient's response, from large validated question banks. This provides brevity and precision equivalent to the entire question bank.
Aim
To evaluate PROMIS CAT tools against ‘legacy instruments’ for cirrhotics and their informal caregivers.
Methods
A total of 200 subjects: 100 cirrhotics (70 men, 53% decompensated) and 100 caregivers were administered the PROMIS and legacy instruments [Sickness Impact Profile (SIP), Beck depression/anxiety inventories, Pittsburgh Sleep-Quality Index (PSQI) and Epworth Sleepiness scale (ESS)] concurrently. Both legacy and PROMIS results for patients were compared with caregivers and US norms. These were also compared between compensated and decompensated patients. Preference for SIP or PROMIS was inquired of a selected group (n = 70, 50% patients). Test – retest reliability was assessed in another group of 20 patients.
Results
Patients had significant impairment on all PROMIS domains apart from anger and anxiety compared with caregivers and US norms (P < 0.02 to <0.0001). Decompensated patients had significantly worse sleep, pain, social and physical function scores compared with compensated ones, similar to legacy instruments. There was a statistically significant correlation between PROMIS and their corresponding legacy instruments. The majority (71%) preferred PROMIS over SIP. PROMIS tools had significant test – retest reliability (ICC range 0.759–0.985) when administered 12 ± 6 days apart.
Conclusion
PROMIS computerised adaptive testing tools had significant concurrent and discriminant validity, test – retest reliability and subject preference for assessing HRQOL in cirrhotic patients.
doi:10.1111/j.1365-2036.2011.04842.x
PMCID: PMC3989141  PMID: 21929591
10.  Prevalence of oesophageal eosinophilia and eosinophilic oesophagitis: a prospective study in unselected patients presenting to endoscopy 
Oesophageal eosinophilia (EE) is encountered in clinical practice as oesophageal biopsies are being obtained in patients with GI symptoms other than classical symptoms of eosinophilic oesophagitis (EoE). The prevalence, determinants and clinical relevance of EE identified irrespective of symptoms are unclear.
Aim
To determine the prevalence and risk factors of EE with or without EoE in a non-selected group of patients undergoing endoscopy and in primary care patients.
Methods
A cross-sectional study in a single VA center in which we obtained at least one oesophageal biopsy from patients presenting to elective endoscopy, as well as a sample of patients eligible for screening colonoscopy recruited from primary care clinics. EE was defined by > 15 eosinophils in a single HPF; and EoE was defined as definite, probable or none depending on the presence of EE, acid-suppressive therapy and oesophageal symptoms.
Results
EE was identified in 33 of 1357 patients (2.4%, 95% CI: 1.7–3.4); of whom 9 had definite EoE (0.66%, 95% CI: 0.23–1.10), 17 had probable EoE (1.25%), and the only 7 patients had EE without EoE. The prevalence of EE was 2.3% among patients undergoing elective endoscopy and 0.1% among patients eligible for screening colonoscopy. Seasonal allergies (adjusted OR: 2.78; 95%CI 1.26 – 6.11) and oesophageal strictures (4.50; 0.90 – 22.40) were associated with EE.
Conclusions
The prevalence of EE was 2.3% among unselected patients presenting to endoscopy most of whom have EoE. EE was present in 0.1% in primary care patients none of whom had EoE.
doi:10.1111/apt.12268
PMCID: PMC3602156  PMID: 23441936
Epidemiology; H. pylori; Dysphagia; Eosinophilia; Risk Factors
11.  Review article: the design of clinical trials in hepatic encephalopathy - an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement 
Summary
Background
The clinical classification of hepatic encephalopathy is largely subjective, which has led to difficulties in designing trials in this field.
Aims
To review the current classification of hepatic encephalopathy and to develop consensus guidelines on the design and conduct of future clinical trials.
Methods
A round table was convened at the 14th International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting. Key discussion points were the nomenclature of hepatic encephalopathy and the selection of patients, standards of care and end-points for assessing the treatment and secondary prevention of hepatic encephalopathy.
Results
It was generally agreed that severity assessment of hepatic encephalopathy in patients with cirrhosis, whether made clinically or more objectively, should be continuous rather than categorical, and a system for assessing the SONIC (Spectrum of Neuro-cognitive Impairment in Cirrhosis) was proposed. Within this system, patients currently classified as having minimal hepatic encephalopathy and Grade I hepatic encephalopathy would be classified as having Covert hepatic encephalopathy, whereas those with apparent clinical abnormalities would continue to be classified as overt hepatic encephalopathy. Some aspects of the terminology require further debate. Consensus was also reached on the patient populations, standards of care and endpoints to assess clinical trial outcomes. However, some compromises had to be made as there is considerable inter- and intravariability in the availability of some of the more objective surrogate performance markers.
Conclusions
The objectives of the round table were met. Robust, defendable guidelines for the conduct of future studies into hepatic encephalopathy have been provided. Outstanding issues are few and will continue to be discussed.
doi:10.1111/j.1365-2036.2011.04590.x
PMCID: PMC3971432  PMID: 21306407
12.  Review article: current treatment options and management of functional dyspepsia 
SUMMARY
Background
Functional dyspepsia (FD), a common functional gastrointestinal disorder, is defined by the Rome III criteria as symptoms of epigastric pain or discomfort (prevalence in FD of 89–90%), postprandial fullness (75–88%), and early satiety (50–82%) within the last 3 months with symptom onset at least 6 months earlier. Patients cannot have any evidence of structural disease to explain symptoms and predominant symptoms of gastroesophageal reflux are exclusionary. Symptoms of FD are non-specific and the pathophysiology is diverse, which explains in part why a universally effective treatment for FD remains elusive.
Aim
To present current management options for the treatment of FD (therapeutic gain/response rate noted when available).
Results
The utility of Helicobacter pylori eradication for the treatment of FD is modest (6–14% therapeutic gain), while the therapeutic efficacy of proton pump inhibitors (PPI) (7–10% therapeutic gain), histamine-type-2-receptor antagonists (8–35% therapeutic gain), prokinetic agents (18–45%), tricyclic antidepressants (TCA) (response rates of 64–70%), serotonin reuptake inhibitors (no better than placebo) is limited and hampered by inadequate data. This review discusses dietary interventions and analyses studies involving complementary and alternative medications, and psychological therapies.
Conclusions
A reasonable treatment approach based on current evidence is to initiate therapy with a daily PPI in H. pylori-negative FD patients. If symptoms persist, a therapeutic trial with a tricyclic antidepressant may be initiated. If symptoms continue, the clinician can possibly initiate therapy with an antinociceptive agent, a prokinetic agent, or some form of complementary and alternative medications, although evidence from prospective studies to support this approach is limited.
doi:10.1111/j.1365-2036.2012.05128.x
PMCID: PMC3970847  PMID: 22591037
13.  Assessment of concordance of symptom reflux association tests in ambulatory pH monitoring 
Alimentary pharmacology & therapeutics  2012;10.1111/j.1365-2036.2012.05066.x.
SUMMARY
Background
Both simple proportions and statistical tests are utilised for symptom-reflux association. We systematically compared three such tests in a clinical setting.
Aim
To compare the three commonly used symptom reflux association tests in a large cohort of patients undergoing ambulatory pH monitoring for the evaluation of oesophageal symptoms.
Methods
Ambulatory pH data from 772 symptomatic subjects (49.1 ± 0.5 years; 479 F) tested off therapy were assessed for acid exposure time (AET, elevated when pH <4 for ≥4%), symptom index (SI, ≥50% when positive), and symptom association probability (SAP) and Ghillebert probability estimate (GPE, P < 0.05 when positive). Test concordance and discordance were individually assessed; discordance between statistical tests was minor if one had P < 0.1 while the other was positive. Logistic regression determined independent predictors of test discordance.
Results
The SAP, GPE and SI were positive in 42.7%, 39.3% and 33.9% respectively. GPE performed extremely well compared to SAP (sensitivity 0.95, specificity 0.91), with major discordance in only 2.8%. Positive concordance was significantly higher when AET was abnormal. GPE underestimated symptom association compared to SAP, whereas SAP was subject to symptom over-counting in 33.3% of discordant cases. GPE-SAP discordance was associated with higher AET (7.5% vs. 5.1%) and more symptoms (19.3 vs. 10.7, P > 0.001 for each comparison with concordant tests); both remained significant on logistic regression analysis (P ≥ 0.003). SI was discordant with SAP when symptoms were extremely frequent (median 19, IQR 10–32) or limited (median 1, IQR 1–2), and concordant when median 6 symptoms (IQR 3–12) were recorded.
Conclusions
The GPE can be used interchangeably with SAP in symptom reflux association. SI has uncertain value with very high and very low symptom counts.
doi:10.1111/j.1365-2036.2012.05066.x
PMCID: PMC3959626  PMID: 22428660
14.  Asimadoline, a kappa-opioid agonist, and satiation in functional dyspepsia 
Alimentary pharmacology & therapeutics  2008;27(11):1122-1131.
SUMMARY
Background
Asimadoline, a kappa-opioid agonist, reduces visceral sensitivity in experimental animal models and may decrease satiation and postprandial fullness in healthy individuals. However, its effect on satiation in functional dyspepsia is unclear, and any symptom benefit has not been explored.
Aim
To evaluate the effects of asimadoline on satiation volume and postchallenge symptoms in functional dyspepsia.
Methods
A randomized, double-blind trial evaluated gastric satiation and symptoms before and after 8 weeks of asimadoline 0.5 mg (n = 13) or 1.0 mg (n = 13) or placebo (n = 14) b.d. in patients with functional dyspepsia (Rome II). Gastrointestinal Symptom Rating Scale and Nepean Dyspepsia Index were used to assess symptoms during the 8-week treatment.
Results
Over 8 weeks of treatment, asimadoline had no significant effect on maximum-tolerated volume or aggregate symptom score with nutrient drink challenge, and on the mean of the total daily symptom severity score compared to placebo. In a post hoc analysis, asimadoline 0.5 mg significantly increased the maximum-tolerated volume (1217 mL ± 90.2) compared to placebo (807 mL ± 111.8) in patients with higher postprandial fullness scores (P = 0.01).
Conclusion
Asimadoline overall did not significantly alter maximum-tolerated volume, symptoms postnutrient challenge or symptoms over 8 weeks in functional dyspepsia.
doi:10.1111/j.1365-2036.2008.03676.x
PMCID: PMC3935285  PMID: 18331462
15.  Systematic review: probiotics in the management of lower gastrointestinal symptoms in clinical practice – an evidence-based international guide 
BackgroundEvidence suggests that the gut microbiota play an important role in gastrointestinal problems.
AimTo give clinicians a practical reference guide on the role of specified probiotics in managing particular lower gastrointestinal symptoms/problems by means of a systematic review-based consensus.
MethodsSystematic literature searching identified randomised, placebo-controlled trials in adults; evidence for each symptom/problem was graded and statements developed (consensus process; 10-member panel). As results cannot be generalised between different probiotics, individual probiotics were identified for each statement.
ResultsThirty seven studies were included; mostly on irritable bowel syndrome [IBS; 19 studies; treatment responder rates: 18–80% (specific probiotics), 5–50% (placebo)] or antibiotic-associated diarrhoea (AAD; 10 studies). Statements with 100% agreement and ‘high’ evidence levels indicated that: (i) specific probiotics help reduce overall symptom burden and abdominal pain in some IBS patients; (ii) in patients receiving antibiotics/Helicobacter pylori eradication therapy, specified probiotics are helpful as adjuvants to prevent/reduce the duration/intensity of AAD; (iii) probiotics have favourable safety in patients in primary care. Items with 70–100% agreement and ‘moderate’ evidence were: (i) specific probiotics help relieve overall symptom burden in some patients with diarrhoea-predominant IBS, and reduce bloating/distension and improve bowel movement frequency/consistency in some IBS patients and (ii) with some probiotics, improved symptoms have led to improvement in quality of life.
ConclusionsSpecified probiotics can provide benefit in IBS and antibiotic-associated diarrhoea; relatively few studies in other indications suggested benefits warranting further research. This study provides practical guidance on which probiotic to select for a specific problem.
doi:10.1111/apt.12460
PMCID: PMC3925990  PMID: 23981066
16.  Review Article: Celiac Disease, New Approaches to Therapy 
STRUCTURED SUMMARY
Background
Celiac disease is managed by life-long gluten withdrawal from the diet. However strict adherence to a gluten-free diet is difficult and is not always effective. Novel therapeutic approaches are needed to supplement or even replace the dietary treatment.
Aims
To review recent advances in new therapeutic options for celiac disease.
Methods
A literature search was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrial.gov for English articles and abstracts. The search terms used include but not limited to “Celiac disease”, “new”, “novel”, Advances”, “alternatives” and “Drug therapy”. The cited articles were selected based on the relevancy to the review objective.
Results
Several new therapeutic approaches for celiac disease are currently under development by targeting its underlying pathogenesis. Alternative therapies range from reproduction of harmless wheat strains to immunomodulatory approaches. Some of these therapies such as enzymatic cleavage of gluten and permeability inhibitors have shown promise in clinical studies.
Conclusion
Gluten-free diet is still the only practical treatment for patients with celiac disease. Novel strategies provide promise of alternative adjunctive approaches to diet restriction alone for patients with this disorder.
doi:10.1111/j.1365-2036.2012.05013.x
PMCID: PMC3912561  PMID: 22324389
gluten; zonulin; inflammation; malabsorption
17.  The interpretation of Rome III criteria and method of assessment affect the irritable bowel syndrome classification of children 
SUMMARY
Background
Paediatric classification of irritable bowel syndrome (IBS) is complicated by the potential discrepancy between parent and child report and by the interpretation of pain-stool relations in the Rome III classification system.
Aim
To compare IBS classification by diary and by child and parent respondents.
Methods
Children (ages 7–10 years, n = 90) with recurrent abdominal pain and their parents completed IBS symptom questionnaires and 2-week pain and stool diaries. Diaries were coded with two algorithms, one defining stool changes individually and one defining changes normatively. Proportions of dichotomous classifications (IBS vs. not IBS) between pairs of classification methods/respondents were evaluated using Chi-squared tests (χ2) to determine whether coding methods were significantly related, the degree of inclusiveness, and whether differences in classification were randomly distributed.
Results
Individual and normative diary classifications were congruent in 62% of cases, but the individual method classified more children with IBS, 53% vs. 18%. Parent and child questionnaire reports were not correlated. The normative diary classifications and parent questionnaire were the most congruent pair of methods (76% of cases).
Conclusions
Poor congruence among methods suggests that Rome III IBS criteria need better specification, and efforts to improve parent-child agreement are necessary.
doi:10.1111/j.1365-2036.2010.04535.x
PMCID: PMC3912994  PMID: 21138454
18.  Psychiatric co-morbidity is Associated with Increased risk of Surgery in Crohn’s disease 
Introduction
Psychiatric co-morbidity, in particular major depression and anxiety is common in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Prior studies examining this may be confounded by the co-existence of functional bowel symptoms. Limited data exists examining an association between depression or anxiety and disease-specific endpoints such as bowel surgery.
Methods
Using a multi-institution cohort of patients with CD and UC, we identified those who also had co-existing psychiatric co-morbidity (major depressive disorder or generalized anxiety). After excluding those diagnosed with such co-morbidity for the first time following surgery, we used multivariate logistic regression to examine the independent effect of psychiatric co-morbidity on IBD-related surgery and hospitalization. To account for confounding by disease severity, we adjusted for a propensity score estimating likelihood of psychiatric co-morbidity influenced by severity of disease in our models.
Results
A total of 5,405 CD and 5,429 UC patients were included in this study; one-fifth had either major depressive disorder or generalized anxiety. In multivariate analysis, adjusting for potential confounders and the propensity score, presence of mood or anxiety co-morbidity was associated with a 28% increase in risk of surgery in CD (OR 1.28, 95% CI 1.03 – 1.57) but not UC (OR 1.01, 95% CI 0.80 – 1.28). Psychiatric co-morbidity was associated with increased healthcare utilization.
Conclusion
Depressive disorder or generalized anxiety is associated with a modestly increased risk of surgery in patients with CD. Interventions addressing this may improve patient outcomes.
doi:10.1111/apt.12195
PMCID: PMC3552092  PMID: 23289600
Crohn’s disease; ulcerative colitis; depression; surgery; hospitalization
19.  Mucosal Healing and Mortality in Celiac Disease 
BACKGROUND AND OBJECTIVES
Celiac disease (CD), characterized by the presence of villous atrophy (VA) in the small intestine, is associated with increased mortality, but it is unknown if this excess mortality is influenced by mucosal recovery. We examined overall mortality according to mucosal recovery in CD.
METHODS
Through biopsy reports from all pathology departments (n=28) in Sweden we identified 7,648 individuals with CD (defined as VA) who had undergone a follow-up biopsy within 5 years following diagnosis. We then used Cox regression to examine overall mortality according mucosal recovery in the follow-up biopsy (persistence of VA vs. recovery).
RESULTS
The mean age of CD diagnosis was 28.4, 63% were female, and the median follow-up after diagnosis was 11.5 years. Of the 7,648 patients, persistent VA was present in 3,317 (43%). There were 606 (8%) deaths. Patients with persistent VA were not at increased risk of death compared to those with mucosal healing (Hazard Ratio 1.01; 95% Confidence Interval 0.86-1.19). Mortality was not increased in children with persistent VA (HR 1.09 95% CI 0.37-3.16) or adults (HR 1.00 95% CI 0.85-1.18), including adults older than age 50 years (HR 0.96 95% CI 0.80-1.14).
CONCLUSION
Persistent VA was not associated with increased mortality in CD in this population followed for a median of 11.5 years. While a follow-up biopsy will determine if there is improvement in histology and allow detection of refractory disease in symptomatic patients, our study suggests that early routine follow up biopsies performed within 5 years does not predict long-term mortality risk.
doi:10.1111/apt.12164
PMCID: PMC3566869  PMID: 23190299
coeliac; death; inflammation; serial biopsy (British spelling of coeliac)
20.  Randomized Clinical Trial: Moderators and Mediators of a Psycho-education Group Intervention on IBS Symptoms 
Alimentary pharmacology & therapeutics  2012;37(3):10.1111/apt.12171.
Summary
Background & aims
Evidence supports the effectiveness of cognitive behavioral approaches in improving IBS symptoms. Duration, cost, and resistance of many patients towards a psychological therapy have limited their acceptance. We evaluated the effectiveness of a psycho-educational intervention on IBS symptoms.
Methods
69 IBS patients (72% female) were randomized to an intervention or a wait-list control group. The IBS class consisted of education on a biological mind body disease model emphasizing self-efficacy and practical relaxation techniques.
Results
Patients in the intervention showed significant improvement on GI symptom severity, visceral sensitivity, depression, and QoL post intervention and most of these gains were maintained at 3 month follow up (Hedge’s g =−.46 to .77). Moderated mediation analyses indicated change in anxiety, visceral sensitivity, QoL and catastrophizing due to the intervention had moderate mediation effects (Hedge’s g= −.38 to −.60) on improvements in GI symptom severity for patients entering the trial with low to average QoL. Also, change in GI symptom severity due to the intervention had moderate mediation effects on improvements in QoL especially patients with low to average levels of QoL at baseline. Moderated mediation analyses indicated mediation was less effective for patients entering the intervention with high QoL.
Conclusions
A brief psycho-educational group intervention is efficacious in changing cognitions and fears about IBS symptoms, and these changes are associated with clinically meaningful improvement in IBS symptoms and QoL. The intervention seems particularly tailored to patients with low to moderate QoL baseline levels.
doi:10.1111/apt.12171
PMCID: PMC3829380  PMID: 23205588
irritable bowel syndrome; quality of life; psycho-education; group intervention
21.  Increased Risk of Herpes Zoster among 108,604 Patients with Inflammatory Bowel Disease 
Alimentary pharmacology & therapeutics  2012;37(4):10.1111/apt.12182.
Background
Patients with inflammatory bowel disease (IBD) on certain immunosuppressants have increased herpes zoster (HZ) risk.
Aim
To determine the risk of HZ in IBD and how anti-tumor necrosis factor-alpha (anti-TNF)agents affect this risk.
Methods
We performed a retrospective cohort and nested case-control study using administrative data from IMS LifeLink® Information Assets-Health Plan Claims Database. In the cohort, we identified IBD patients < age 64 by diagnosis codes; matched to 4 individuals without IBD. HZ risk was evaluated by incidence rate ratio (IRR) and adjusted Cox proportional hazards models (HR). In the nested case-control analysis, 2,659 IBD patients with HZ were each matched to 4 IBD patients without HZ. We determined associations between medications and HZ using conditional logistic regression.
Results
The cohort included 50,932 patients with Crohn’s disease (CD), 56,403 patients with ulcerative colitis (UC), and 1,269 with unspecified IBD, matched to 434,416 individuals without IBD. The IBD cohort had increased HZ risk compared to non-IBD (IRR 1.68, 95% CI 1.60-1.76). After adjustment, IBD patients had a higher risk of HZ than non-IBD (HR 1.49, 95% CI 1.42-1.57). In the nested case-control multivariate adjusted analyses, anti-TNF medications (OR 1.81, 95% CI 1.48-2.21), corticosteroids (OR 1.73, 95% CI 1.51-1.99) and thiopurines (OR 1.85, 95% CI 1.61-2.13) were independently associated with HZ. Risk of HZ was highest with combination anti-TNF and thiopurine therapy (OR 3.29, 95% CI 2.33-4.65).
Conclusions
Patients with IBD are at increased risk for HZ. Use of thiopurines, anti-TNF agents, combination therapy, and corticosteroids increases HZ risk.
doi:10.1111/apt.12182
PMCID: PMC3886551  PMID: 23240738
inflammatory bowel disease; complications; infections; zoster
22.  The antiviral effect of sorafenib in hepatitis c-related hepatocellular carcinoma 
Background and Aim
Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In-vitro data suggest that sorafenib may exert antiviral properties and thus our aim in this study, was to evaluate potential antiviral activity of sorafenib in patients with HCV-related HCC.
Methods
We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to six months. Baseline clinical, viral, and oncologic data were collected. Patients’ HCV viral loads were obtained at various timepoints, and compared to their baseline viral levels. No patients received any known antiviral therapy during this time.
Results
Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed six months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, C.I. = −0.1799 to 0.8799, p = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumor response to sorafenib showed no significant changes at any time point.
Conclusion
Despite preclinical data and previous subgroup analyses suggesting that sorafenib has antiviral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.
doi:10.1111/apt.12098
PMCID: PMC3682667  PMID: 23094860
hepatitis; viral suppression; hepatoma; virological response; cirrhosis
23.  Stool DNA Testing for the Detection of Colorectal Neoplasia in Patients with Inflammatory Bowel Disease 
Alimentary pharmacology & therapeutics  2013;37(5):10.1111/apt.12218.
Summary
Background
Current approaches to the detection of colorectal neoplasia associated with inflammatory bowel disease (IBD-CRN) are suboptimal.
Aim
We tested the feasibility of using stool assay of exfoliated DNA markers to detect IBD-CRN.
Methods
This investigation comprised tissue and stool studies. In the tissue study, gene sequencing and methylation assays were performed on candidate genes using tissue DNA from 25 IBD-CRNs and from 25 IBD mucosae without CRN. Mutations on P53, APC, KRAS, BRAF or PIK3CA genes were insufficiently informative, but several aberrantly methylated genes were highly discriminant. In the stool study, we evaluated candidate methylated genes (vimentin, EYA4, BMP3, NDRG4) in a prospective blinded study on buffered stools from 19 cases with known IBD-CRN and 35 age- and sex-matched IBD controls without CRN. From stool-extracted DNA, target genes were assayed by quantitative allele-specific real-time target and signal amplification method.
Results
IBD-CRN cases included 17 with ulcerative colitis (UC) and 2 with Crohn’s disease (CD); 9 had cancer and 10 had dysplasia. Controls included 25 with UC and 10 with CD. Individually, BMP3, vimentin, EYA4, and NDRG4 markers showed high discrimination in stools with respective areas under the ROC curve of 0.91, 0.91, 0.85, and 0.84 for total IBD-CRN and of 0.97, 0.97, 0.95, and 0.85 for cancer. At 89% specificity, the combination of mBMP3 and mNDRG4 detected 9/9 (100%) of CRC and 80% of dysplasia, 4/4 (100%) of high grade and 4/6 (67%) of low grade.
Conclusion
These findings demonstrate feasibility of stool DNA testing for noninvasively detecting IBD-CRN.
doi:10.1111/apt.12218
PMCID: PMC3869396  PMID: 23347191
Stool DNA; inflammatory bowel disease; cancer surveillance; colorectal neoplasms; DNA methylation
24.  Epidemiology and Practice Patterns of Achalasia in a Large Multi-Center Database 
Alimentary pharmacology & therapeutics  2011;33(11):10.1111/j.1365-2036.2011.04655.x.
Background and Aims
Because of its rarity, achalasia remains a difficult disease to study. The aim of the present analysis was to describe the epidemiology of achalasia and practice patterns in its endoscopic management, utilizing patient records from a large national database of endoscopic procedures.
Methods
The Clinical Outcomes Research Initiative (CORI) maintains a database of endoscopic procedures in diverse clinical practices. The data from 89 endoscopy practices distributed throughout the US during 2000–2008 were used to analyze the characteristics and therapy of patients with achalasia.
Results
Among 521,497 upper endoscopies during the study period, we identified 896 patients with achalasia. Compared with the entirety of all other endoscopic diagnoses, achalasia was more common in men than women (OR=1.39, CI 1.22–1.59), but similar among non-whites and whites (OR=0.87, CI 0.74–1.03). Relatively more achalasia patients were treated at university than community practices (OR=1.52, CI 1.30–1.78). Botox injection was most frequently used as first choice of endoscopic therapy in 41%, followed by balloon dilation in 21%, Savary dilation in 20%, Maloney dilation in 10%, Rigiflex in 4%, and other modalities in 4% of patients. One quarter of achalasia patients treated endoscopically underwent a repeat therapy about every 14 months.
Conclusions
Botox has become the primary choice of initial endoscopic therapy in achalasia. Despite their partial deviation from guidelines and recommendations, these endoscopic patterns reflect the current clinical practice in the United States.
doi:10.1111/j.1365-2036.2011.04655.x
PMCID: PMC3857989  PMID: 21480936
Achalasia; Botox injection; epidemiology; pneumatic dilation; practice patterns
25.  The effect of varying acidity on helicobacter pylori growth and the bactericidal efficacy of ampicillin 
Summary
Background
Penicillins inhibit cell wall synthesis; therefore, H. pylori must be dividing for this class of antibiotics to be effective in eradication therapy. Identifying growth responses to varying medium pH may allow design of more effective treatment regimens.
Aim
To determine the effect of acidity on bacterial growth and the bactericidal efficacy of ampicillin.
Methods
H. pylori were incubated in dialysis chambers suspended in 1.5L of media at various pHs with 5mM urea, with or without ampicillin, for 4, 8 or 16 hours, thus mimicking unbuffered gastric juice. Changes in gene expression, viability and survival were determined.
Results
At pH 3.0, but not at pH 4.5 or 7.4, there was decreased expression of ~400 genes, including many cell envelope biosynthesis, cell division and penicillin-binding protein genes. Ampicillin was bactericidal at pH 4.5 and 7.4 but not at pH 3.0.
Conclusion
Ampicillin is bactericidal at pH 4.5 and 7.4, but not at pH 3.0, due to decreased expression of cell envelope and division genes with loss of cell division at pH 3.0. Therefore, at pH 3.0, the likely pH at the gastric surface, the bacteria are non-dividing and persist with ampicillin treatment. A more effective inhibitor of acid secretion that maintains gastric pH near neutrality for 24 hours/day should enhance the efficacy of amoxicillin, improving triple therapy and likely even allowing dual amoxicillin based therapy for H. pylori eradication.
doi:10.1111/apt.12059
PMCID: PMC3474890  PMID: 23009227
Helicobacter pylori; medium pH; bacterial growth; ampicillin/amoxicillin; gastric acid inhibition; proton pump inhibitor

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