Introduction of the Concept of Diagnostic Sensitivity and Specificity of Normothermic Perfusion Protocols to Assess High-Risk Donor Livers.

Normothermic machine perfusion (NMP) allows objective assessment of donor liver transplantability. Several viability evaluation protocols have been established, consisting of parameters such as perfusate lactate clearance, pH, transaminase levels, and the production and composition of bile. The aims of this study were to assess 3 such protocols, namely, those introduced by the teams from Birmingham (BP), Cambridge (CP), and Groningen (GP), using a cohort of high-risk marginal livers that had initially been deemed unsuitable for transplantation and to introduce the concept of the viability assessment sensitivity and specificity. To demonstrate and quantify the diagnostic accuracy of these protocols, we used a composite outcome of organ use and 24-month graft survival as a surrogate endpoint. The effects of assessment modifications, including the removal of the most stringent components of the protocols, were also assessed. Of the 31 organs, 22 were transplanted after a period of NMP, of which 18 achieved the outcome of 24-month graft survival. The BP yielded 94% sensitivity and 50% specificity when predicting this outcome. The GP and CP both seemed overly conservative, with 1 and 0 organs, respectively, meeting these protocols. Modification of the GP and CP to exclude their most stringent components increased this to 11 and 8 organs, respectively, and resulted in moderate sensitivity (56% and 44%) but high specificity (92% and 100%, respectively) with respect to the composite outcome. This study shows that the normothermic assessment protocols can be useful in identifying potentially viable organs but that the balance of risk of underuse and overuse varies by protocol.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

Gastroprotection in low-dose aspirin users for primary and secondary prevention of ACS: results of a cost-effectiveness analysis including compliance.

PURPOSE: Low-dose aspirin (ASA) increases the risk of upper gastrointestinal (GI) complications. Proton pump inhibitors (PPIs) reduce these upper GI side effects, yet patient compliance to PPIs is low. We determined the cost-effectiveness of gastroprotective strategies in low-dose ASA users considering ASA and PPI compliance. METHODS: Using a Markov model we compared four strategies: no medication, ASA monotherapy, ASA+PPI co-therapy and a fixed combination of ASA and PPI for primary and secondary prevention of ACS. The risk of acute coronary syndrome (ACS), upper GI bleeding and dyspepsia was modeled as a function of compliance and the relative risk of developing these events while using medication. Costs, quality adjusted life years and number of ACS events were evaluated, applying a variable risk of upper GI bleeding. Probabilistic sensitivity analyses were performed. RESULTS: For our base case patients using ASA for primary prevention of ACS no medication was superior to ASA monotherapy. PPI co-therapy was cost-effective (incremental cost-effectiveness ratio [ICER] €10,314) compared to no medication. In secondary prevention, PPI co-therapy was cost-effective (ICER €563) while the fixed combination yielded an ICER < €20,000 only in a population with elevated risk for upper GI bleeding or moderate PPI compliance. PPI co-therapy had the highest probability to be cost-effective in all scenarios. PPI use lowered the overall number of ACS. CONCLUSIONS: Considering compliance, PPI co-therapy is likely to be cost-effective in patients taking low dose ASA for primary and secondary prevention of ACS, given low PPI prices. In secondary prevention, a fixed combination seems cost-effective in patients with elevated risk for upper GI bleeding or in those with moderate PPI compliance. Both strategies reduced the number of ACS compared to ASA monotherapy.

Differentiation of eight phenotypes and discovery of potential biomarkers for a single plant organ class using laser electrospray mass spectrometry and multivariate statistical analysis.

Laser electrospray mass spectrometry (LEMS) coupled with offline multivariate statistical analysis is used to discriminate eight phenotypes from a single plant organ class and to find potential biomarkers. Direct analysis of the molecules from the flower petal is enabled by interfacing intense (10(13) W/cm(2)), nonresonant, femtosecond laser vaporization at ambient pressure with electrospray ionization for postionization of the vaporized analytes. The observed mass spectral signatures allowed for the discrimination of various phenotypes using principal component analysis (PCA) and either linear discriminant analysis (LDA) or K-nearest neighbor (KNN) classifiers. Cross-validation was performed using multiple training sets to evaluate the predictive ability of the classifiers, which showed 93.7% and 96.8% overall accuracies for the LDA and KNN classifiers, respectively. Linear combinations of significant mass spectral features were extracted from the PCA loading plots, demonstrating the capability to discover potential biomarkers from the direct analysis of tissue samples.

Can museum egg specimens be used for proteomic analyses?

BACKGROUND: Mass spectrometry and proteomic analyses have become powerful tools for the analysis of proteins and peptides. Investigation of proteins contained in the various layers of the avian eggshell has focused entirely on domesticated species. It has been widely assumed that this existing research can inform the study of wild bird species despite the fact that the vast majority of the diversity in avian species (~95%) exists outside the Orders to which domestic and poultry species belong. Museum collections offer a potentially valuable source of material for studying composition of wild avian eggshell matrix proteins. We used museum and fresh eggshells of common quails Coturnix coturnix to compare the protein composition of their organic matrices. Four eggs of domestic chickens were analysed simultaneously as a control for comparison to the fresh and museum quail eggs. The determination of the proteins was carried out using enzymatic cleavage followed by high-performance mass spectrometry. RESULTS: We found that some of the expected key eggshell proteins (3 out of 11) were not present in the samples of museum quail egg. These proteins were either entirely absent from the museum eggs or the technique was unable to detect them. There was no pattern in the absent proteins in the sense of protein function or where they are located within the eggshell. CONCLUSION: We conclude it is likely that such studies on museum specimens using a proteomic approach will be limited in coverage of proteins and may, therefore, be misleading.

Review article: gastrointestinal bleeding with low-dose aspirin - what's the risk?

This review examines ulcers and gastrointestinal bleeding with low-dose aspirin, focusing on randomized placebo-controlled trials. The single endoscopic trial assessing ulcers showed no significant difference in 12-week ulcer incidence: 6% of 381 given placebo vs. 7% of 387 given 81 mg enteric-coated aspirin. The relative risk of major gastrointestinal bleeding with low-dose aspirin in a meta-analysis of placebo-controlled trials of vascular protection was 2.07 (95% CI: 1.61-2.66). The absolute rate increase with aspirin above placebo was 0.12% per year (95% CI: 0.07-0.19%) with a number-needed-to-harm of 833 patients (95% CI: 526-1429). A meta-analysis of aspirin 50-1500 mg daily reported an odds ratio for any gastrointestinal bleeding of 1.68 (95% CI: 1.51-1.88) with an number-needed-to-harm at 1 year of 247. The relative risk of hospitalization for upper gastrointestinal bleeding with low-dose aspirin in a large Danish cohort study was 2.6 (95% CI: 2.2-2.9) with an absolute annual incidence of 0.6%. Factors that may increase the risk of gastrointestinal bleeding include prior history of ulcers or gastrointestinal bleeding, corticosteroid use, anticoagulant therapy and addition of a non-aspirin non-steroidal anti-inflammatory drug. When determining whether low-dose aspirin is appropriate for an individual patient, the cardiovascular benefit must be weighed against the potential for clinical events such as gastrointestinal bleeding.

Systematic review: the lower gastrointestinal adverse effects of non-steroidal anti-inflammatory drugs.

BACKGROUND: Lower gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs) are much more poorly characterized than upper gastrointestinal effects. AIM: To determine if NSAIDs increase lower gastrointestinal adverse effects and if the risk with non-selective NSAIDs is greater than with cyclooxygenase-2-selective inhibitors (coxibs). METHODS: Computerized databases were searched to identify studies of NSAID use reporting on lower gastrointestinal integrity (e.g. permeability), visualization (e.g. erosions, ulcers) and clinical events. RESULTS: Designs in 47 studies were randomized (18), case-control (14), cohort (eight) and before-after (seven). Non-selective-NSAIDs had significantly more adverse effects vs. no NSAIDs in 20 of 22 lower gastrointestinal integrity studies, five of seven visualization studies, seven of 11 bleeding studies (OR: 1.9-18.4 in case-control studies), two of two perforation studies (OR: 2.5-8.1) and five of seven diverticular disease studies (OR: 1.5-11.2). Coxibs had significantly less effect vs. non-selective-NSAIDs in three of four integrity studies, one endoscopic study (RR mucosal breaks: 0.3), and two randomized studies (RR lower gastrointestinal clinical events: 0.5; haematochezia: 0.4). CONCLUSIONS: An increase in lower gastrointestinal injury and clinical events with non-selective-NSAIDs appears relatively consistent across the heterogeneous collection of trials. Coxibs are associated with lower rates of lower gastrointestinal injury than non-selective-NSAIDs. More high-quality trials are warranted to more precisely estimate the effects of non-selective-NSAIDs and coxibs on the lower gastrointestinal tract.

Effect of frequent dosing of an oral proton pump inhibitor on intragastric pH.

BACKGROUND: Treatment with a continuous i.v. proton pump inhibitor is presumed to promote clot formation and stability by sustaining intragastric pH > or = 6. AIM: We postulated that very frequent oral dosing of proton pump inhibitors should simulate i.v. infusion and achieve similar pH control. METHODS: Twenty healthy volunteers were stratified by Helicobacter pylori status (10 positive; 10 negative) and had determination of CYP2C19 status. After an overnight fast, an intragastric pH probe was placed. Subjects received 120 mg of lansoprazole at 8 am and 30 mg every 3 h until 8 pm. Intragastric pH was measured over 24 h, and lansoprazole plasma concentrations were determined at five time points. RESULTS: Intragastric pH was > or = 6 for 41% (95% CI: 30-53%) of the 15-h period from 8 am-11 pm and 46% (95% CI: 35-56%) of the 24-h period (8-8 am). The mean proportion of patients with pH > or = 6 was not significantly different in H. pylori-positive vs. negative patients. Only 25% of subjects sustained pH > or = 6 for at least 60% of the 15-h period, and 35% had a sustained pH > or = 6 for at least 60% of the 24-h period. CONCLUSIONS: A dose of 120 mg of oral lansoprazole followed by standard 30 mg doses of lansoprazole every 3 h did not reliably sustain pH at the desired level of 6.

Preoperative systemic chemotherapy followed by adjuvant postoperative intraperitoneal therapy for gastric cancer: a University of Southern California pilot program.

PURPOSE: A clinical trial for patients with gastric cancer amenable to curative resection was undertaken to determine feasibility and response to preoperative systemic chemotherapy followed by postoperative intraperitoneal (IP) chemotherapy. METHODS AND MATERIALS: Thirty-eight patients with resectable gastric tumor received two cycles of protracted intravenous (IV)-infusion fluorouracil (5FU), 200 mg/m2/d, for 3 weeks with weekly IV leucovorin 20 mg/m2 and IV cisplatin 100 mg/m2 days 1 and 29. Resection of the gastric tumor followed within 3 weeks of completion of systemic chemotherapy. Those who had all visible tumor removed with clear margins received two cycles of IP floxuridine 3,000 mg (total dose) per day for 3 days and IP cisplatin 200 mg/m2 with IV sodium thiosulfate on the fourth day of IP therapy. RESULTS: Thirty-seven of 38 patients (97%) received two cycles of systemic chemotherapy. Thirty-five of 38 patients (92%) underwent laparotomy for gastric tumor resection. Thirty-three patients (87%) had gastric resections performed; 29 (76%) had all visible tumor removed with microscopically negative margins. No operative mortality was encountered. Twenty-six patients (68%) received IP treatment. IV neoadjuvant treatment was well tolerated and resulted in 68% of the patients reporting improvement in abdominal pain, 45% objective remissions by computed tomography (CT), 38% objective remissions by gastroscopy and biopsy, and 8% had complete surgical pathologic response. Neutropenic sepsis during the IP treatment phase contributed to the only treatment-related death. Four of 29 completely resected patients (14%) have had tumor recurrence. The median follow-up time of patients remaining alive is now 19 months. The median survival for 38 patients entered onto this protocol has not been reached at 17+ months. CONCLUSION: This novel approach to the treatment of adenocarcinoma of the stomach is feasible. The neoadjuvant systemic therapy results in significant primary tumor regression. The determination of whether systemic or IP components of the program contribute to decreased recurrence or increased survival awaits a prospectively randomized clinical trial.

Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival.

PURPOSE: We tested the hypothesis that polymerase chain reaction (PCR) quantitation of the enzyme thymidylate synthase (TS) within a primary adenocarcinoma of the stomach, has an inverse relationship to response and survival for patients who receive fluorouracil (5FU)-based chemotherapy. PATIENTS AND METHODS: Before systemic chemotherapy, the genetic expression of TS (TSmRNA level) was determined using a PCR method. Gene expression was calculated by determining the ratio between the amount of radiolabeled PCR product with the linear amplification range of the TS gene and the beta-actin gene. Chemotherapy consisted of two cycles of protracted infusion (PI) 5FU 200 mg/m2/d administered for 3 weeks with leucovorin 20 mg/m2/w. Cisplatin 100 mg/m2 was administered on day 1. RESULTS: Sixty-five patients with primary gastric cancer had a median TS mRNA level of 4.6 x 10(-3) (range, 0.9 to 20.1 x 10(-3)). Thirty-five percent of patients had measurable responses in their primary tumors. The mean gastric cancer TSmRNA level in responding and resistant patients is statistically significant (P < .001). The median survival time was 43+ months for treated patients with TSmRNA levels less than the median and 6 months for those with TS m-RNA levels greater than the median (P = .003). CONCLUSION: The genetic expression of TS (TSmRNA level) influences response to 5FU-based chemotherapy and survival for a cohort of patients with primary gastric cancer. Confirmation of these data could lead to therapeutic decisions based on specific molecular properties within a tumor.

ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy.

PURPOSE: We have previously shown that relative thymidylate synthase (TS) mRNA levels in primary gastric adenocarcinomas treated with fluorouracil (5-FU) and cisplatin are inversely associated with response and survival. This is a presumed function of TS as a target for 5-FU activity. We now test the hypotheses that the relative mRNA level of the excision repair cross-complementing (ERCC1) gene is inversely associated with response and survival as an independent function of cisplatin efficacy. PATIENTS AND METHODS: Patients had intact, untreated, primary gastric adenocarcinoma cancer and were evaluated for eligibility on a preoperative cisplatin infusion-5-FU protocol. cDNA, derived from primary gastric tumors before chemotherapy, was used to determine ERCC1 mRNA levels, expressed as the ratio of polymerase chain reaction (PCR) product of the ERCC1 gene and the beta-actin gene. RESULTS: The median ERCC1 mRNA level from 38 primary gastric cancers (33 assessable for response) was 5.8 x 10(-3) (range, 1.8 x 10(-3) to 19.5 x 10(-3)). Of 17 responding patients, 13 (76%) were less than or equal to 5.8 x 10(-3) and four were greater than 5.8 x 10(-3) (P = .003). The median survival for patients with ERCC1 mRNA levels less than or equal to 5.8 x 10(-3) has not been reached, whereas for those greater than 5.8 x 10(-3) it was 5.4 months (P = .034). The median TS mRNA level, 3.7 x 10(-3) (range, 0.9 to 18.9) also segregated responsive versus resistant tumors (P = .024). With both ERCC1 and TS mRNA levels below their medians, 11 of 13 patients (85%) responded; with both ERCC1 and TS mRNA levels above their medians, two of 10 patients (20%) responded (P = .003). CONCLUSION: Considered separately, either ERCC1 or TS mRNA levels in a primary gastric adenocarcinoma has a statistically significant relationship to response. ERCC1 mRNA levels have a statistically significant association with survival; in this cohort TS mRNA levels did not reach statistically significant association with survival as in our previous publication. Whether these molecular parameters are independent of each other as predictors of outcome remains to be determined.

Esophageal candidiasis in patients infected with the human immunodeficiency virus. A decision analysis to assess cost-effectiveness of alternative management strategies.

BACKGROUND: Currently no consensus exists concerning the timing of upper endoscopy and the choice of antifungal therapy for patients infected with the human immunodeficiency virus who also have esophageal candidiasis. The objective of this research was to determine the clinical and economic effects of alternative management strategies for these patients. METHODS: Decision analysis was used to evaluate the outcomes, costs, and cost-effectiveness of two strategies for the diagnostic workup and treatment of patients infected with the human immunodeficiency virus with dysphagia and/or odynophagia: (1) empiric--a strategy to treat all patients empirically with an oral antifungal agent for up to 4 weeks; and (2) initial esophagogastroduodenoscopy (EGD)--a strategy to perform EGD on all patients and to treat only those with esophageal candidiasis with an oral antifungal agent for up to 4 weeks. Within each strategy, three antifungal regimens were evaluated: ketoconazole, 200 mg daily; fluconazole, 100 mg daily; and ketoconazole, 200 mg daily, for 2 weeks followed by fluconazole, 200 mg daily, for 2 weeks in nonresponders. Information on the probability of esophageal candidiasis in patients with esophageal symptoms and the efficacy of antifungal therapy was obtained from the literature. The costs for diagnostic workup were estimated using both teaching hospital charges and Medicare reimbursement payments. The costs of antifungal therapy were estimated from local pharmacy charges. The average cost per complete response and incremental cost-effectiveness were calculated and subjected to sensitivity analysis. RESULTS: Using the best available evidence for antifungal efficacy, empiric fluconazole was the most cost-effective strategy for all probabilities of esophageal candidiasis that were more than 0.55. Using teaching hospital charges in our base-case analysis, the average costs per complete response for empiric fluconazole and initial EGD and fluconazole were $2706 and $3141, respectively. The incremental cost-effectiveness of initial EGD and fluconazole compared with empiric fluconazole was $3792 per additional complete response. When the cost-effectiveness of the two strategies was compared as the cost of diagnostic workup was varied, initial EGD and fluconazole became the dominant strategy when the diagnostic workup cost fell below $710, a figure that is less than the current Medicare reimbursement payment. CONCLUSIONS: From the perspective of the payer of medical care, empiric fluconazole is the most cost-effective strategy for the initial management of patients infected with the human immunodeficiency virus with esophageal symptoms.

Esophageal disease in human immunodeficiency virus infection.

Up to 40% of patients with the acquired immunodeficiency syndrome may develop symptoms of esophageal disease. Candida esophagitis is responsible for the majority of the cases of esophageal disease; cytomegalovirus, herpes simplex, idiopathic esophageal ulcers, and Kaposi's sarcoma account for most of the remaining cases. Although endoscopy with esophageal biopsy and brushing is the gold standard for the diagnosis of esophageal disease in the acquired immunodeficiency syndrome, we generally recommend initial empiric therapy with an antifungal agent in patients with esophageal symptoms. Since effective treatment is available for most cases of esophageal disease in the acquired immunodeficiency syndrome, we recommend endoscopic evaluation in patients who do not respond to empiric therapy within 1 to 2 weeks.

The causes of esophageal symptoms in human immunodeficiency virus infection. A prospective study of 110 patients.

STUDY OBJECTIVES: --To determine the prevalence of infectious agents in patients with human immunodeficiency virus infection and odynophagia or dysphagia; the utility of endoscopic, histologic, cytologic, and virologic testing for the diagnosis of esophagitis; and the yield of blind brushings of the esophagus in this setting. DESIGN: --Prospective clinical case study. SETTING: --Urban county hospital. PATIENTS: --One hundred ten consecutive patients with esophageal symptoms and documented human immunodeficiency virus infection. INTERVENTION: --Blind brushing of the esophagus via orogastric tube followed by endoscopy with esophageal brushing for fungal stain, Papanicolau smear, and viral cultures and esophageal biopsies for histologic examination and viral culture. MAIN RESULTS: --Seventy-two (65%) of the 110 patients had a total of 100 esophageal infections. Thirty-three (30%) had Candida alone, 22 (20%) had Candida and cytomegalovirus, two (1.8%) had Candida with cytomegalovirus and herpes simplex virus, seven (6%) had cytomegalovirus alone, six (5%) had herpes simplex virus alone, and two (1.8%) had both viruses. Fifty of 55 patients with plaques alone had Candida, and two (4%) had only viral infection. Of 19 patients with erosions or ulcers, 11 (58%) had a viral infection, two (11%) had Candida alone, and six (30%) had no etiologic agent identified. The sensitivity of endoscopic brushings (95%) was better than that of histologic examination (70%) in the diagnosis of Candida esophagitis. Likewise, viral cultures of brushings or biopsy specimens were more sensitive (67%) than histologic examination (35%) for viral esophagitis. Blind brushing of the esophagus had a sensitivity and specificity for infectious esophagitis of 84% and 75%, respectively. Oral thrush had a sensitivity of 53% and a positive predictive value of 77% for Candida esophagitis.

Protein-losing enteropathy in acquired immunodeficiency syndrome due to intestinal Kaposi's sarcoma.

Patients with the acquired immunodeficiency syndrome (AIDS) often have hypoalbuminemia. We report the case of a patient with AIDS in whom marked hypoalbuminemia developed due to a protein-losing enteropathy caused by small intestinal Kaposi's sarcoma--an entity not previously reported in AIDS. The patient presented with ankle edema, pleural effusions, and a decrease in albumin from 3.0 g/dL (30 g/L) to 1.7 g/dL (17 g/L) over one month. Protein-losing enteropathy was confirmed by a marked elevation in fecal alpha-1 antitrypsin, and extensive evaluation of the gastrointestinal tract revealed the source to be small intestinal Kaposi's sarcoma. A protein-losing enteropathy should be considered when hypoalbuminemia is encountered in a patient with AIDS.

Helicobacter pylori-related disease: guidelines for testing and treatment.

OBJECTIVE: To develop practical guidelines for the treatment of patients with suspected and documented Helicobacter pylori-related gastroduodenal diseases. METHODS: A panel of physicians with expertise in H. pylori reviewed, critically appraised, and synthesized the literature on assigned topics and presented their overviews to the panel. Consensus was obtained in controversial areas through discussion. RESULTS AND CONCLUSIONS: The panel recommended testing for H. pylori in patients with active ulcers, a history of ulcers, or gastric mucosa-associated lymphoid tissue lymphomas. Young, otherwise healthy patients with ulcerlike dyspepsia and those with a family history or fear of gastric cancer may also undergo H pylori testing. Non-endoscopic methods are preferred for H. pylori diagnosis. Dual medication regimens should not be used for therapy; twice-daily triple therapy with a proton pump inhibitor or ranitidine bismuth citrate, clarithromycin, and amoxicillin for 10 to 14 days is an appropriate therapy. Posttreatment assessment of H. pylori status using urea breath testing should be considered in patients with a documented history of ulcer disease or with persistent symptoms.

Delayed endoscopic retrograde cholangiopancreatography is associated with persistent organ failure in hospitalised patients with acute cholangitis.

BACKGROUND: Predictors of organ failure and the impact of early endoscopic retrograde cholangiopancreatography (ERCP) on outcomes in patients with acute cholangitis are unclear. AIM: To identify factors associated with persistent organ failure and assess the impact of early ERCP on outcomes in hospitalised patients with cholangitis. METHODS: Consecutive hospitalised patients who received ERCP at two centres for cholangitis from 4/2005-3/2013 were retrospectively reviewed. Delayed ERCP was defined as ERCP ≥ 48 h after hospitalisation. Primary outcome was persistent organ failure at >48 h after hospitalisation (≥ 1.5 times rise in creatinine levels from baseline values to ≥ 1.5 mg/dL or need for dialysis, mechanical ventilation and/or hypotension requiring vasopressor). RESULTS: 203 patients (mean age 59 ± 19 years) had ERCP for cholangitis: 115 with choledocholithiasis, 48 with other benign obstructions and 40 with malignant strictures. Forty-five (22%) patients had persistent organ failure at >48 h and 11 (5%) died. On multivariate analysis, Charlson Comorbidity Index >2 (OR = 4.6, 95% CI = 1.5-13.8), systemic inflammatory response syndrome (SIRS; OR = 3.2, 95% CI = 1.1-9.8), hypoalbuminemia (OR = 3.3, 95% CI = 1.4-7.9), bacteremia (OR = 2.8, 95% CI 1.3-6.2) and delayed ERCP(OR = 3.1, 95% CI: 1.4-7.0) were associated with persistent organ failure. Every 1-day delay in ERCP was associated with a 17% (95% CI = 5-29%) relative risk increase in persistent organ failure after adjusting for significant factors. CONCLUSIONS: Delay in ERCP beyond 48 h was associated with persistent organ failure in hospitalised patients with acute cholangitis. Other factors included increased comorbidities, SIRS, hypoalbuminemia and bacteremia. Early ERCP performed within 48 h after presentation in patients with cholangitis may improve outcomes.

The effects of proton pump inhibition on patient-reported severity of dyspepsia when receiving dual anti-platelet therapy with clopidogrel and low-dose aspirin: analysis from the Clopidogrel and the Optimization of Gastrointestinal Events Trial.

BACKGROUND: Dual anti-platelet therapy with clopidogrel and low-dose aspirin increases the risk for gastrointestinal clinical events. Omeprazole has been shown to significantly reduce these events without compromising cardiovascular safety in patients treated with dual anti-platelet therapy. Whether or not omeprazole improves patient-reported outcomes is undetermined. AIM: To assess the impact of prophylactic omeprazole with background dual anti-platelet therapy on patient-reported symptoms of dyspepsia compared to placebo. METHODS: We analysed results of the Severity of Dyspepsia Assessment questionnaires collected in the Clopidogrel and the Optimization of Gastrointestinal Events Trial. RESULTS: Patient-reported outcome data from 3759 subjects were available for analysis. At 4 weeks, the mean scores of pain intensity and nonpain symptoms were lower in the omeprazole group (5.61 ± 0.17 vs. 6.40 ± 0.17, P = 0.001, and 10.61 ± 0.07 vs. 11.00 ± 0.07, P < 0.001 respectively). These differences were maintained at 24 weeks (5.91 ± 0.35 vs. 7.10 ± 0.37, P = 0.020 for pain intensity; 10.36 ± 0.12 vs. 10.93 ± 0.13, P = 0.001 for nonpain symptoms). After adjusting for covariates there were no statistically significant differences between the groups in the percent of patients with dyspepsia during follow-up. CONCLUSIONS: In addition to reducing the risk of gastrointestinal bleeding, statistically significant benefits with prophylactic omeprazole use on both pain and nonpain symptoms were evident at 4 weeks and sustained through 24 weeks. The clinical significance of these overall results is unclear, but greater in patients with pain at baseline.

Protein-losing enteropathy and hypoalbuminemia in AIDS.

OBJECTIVE: To assess the contribution of protein-losing enteropathy to AIDS-associated hypoalbuminemia. DESIGN: Prospective assessment of patients with AIDS. SETTING: An urban county hospital (Los Angeles & University of Southern California Medical Center. USA). PATIENTS: Four groups of patients with AIDS were studied: (1) patients with normal serum albumin (> or = 3.9 g/dl) and normal bowel habits; (2) patients with normal serum albumin and diarrhea (> or = four loose or watery stools per day for > or = 2 weeks); (3) patients with hypoalbuminemia (< or = 3.0 g/dl) and normal bowel habits; and (4) patients with hypoalbuminemia and diarrhea. MAIN OUTCOME MEASURE: Fecal alpha 1-antitrypsin concentration was used as a measure of protein loss in the gut. RESULTS: Patients with hypoalbuminemia had a significantly higher mean fecal alpha 1-antitrypsin concentration than those with normal albumin (10.8 +/- 3.0 mg/g dry stool versus 2.4 +/- 0.4 mg/g dry stool; P < or = 0.001). Although mean fecal alpha 1-antitrypsin concentrations were similar in patients with and without diarrhea in the normal albumin group, patients with hypoalbuminemia and diarrhea had significantly higher levels of fecal alpha 1-antitrypsin than those with hypoalbuminemia and normal bowel habits (17.3 +/- 5.8 mg/g dry stool versus 4.6 +/- 1.0 mg/g dry stool; P = 0.009). Twelve out of 36 (33%) patients with normal albumin had elevation of fecal alpha 1-antitrypsin compared with 33 (70%) of 47 patients with hypoalbuminemia (P < or = 0.001). Linear regression analysis showed a significant negative correlation between serum albumin and fecal alpha 1-antitrypsin concentration (r = -0.38; P < or = 0.001). Fecal alpha 1-antitrypsin was significantly higher in patients with mucosal disease visualized at upper endoscopy or flexible sigmoidoscopy than in those without gross abnormalities (13.5 +/- 5.8 mg/g dry stool versus 2.4 +/- 0.7 mg/g dry stool; P = 0.005). CONCLUSION: Protein-losing enteropathy is common in patients with AIDS and may contribute to the development of hypoalbuminemia in these patients.

Cysteine usage increases the need for acetate in neonates who receive total parenteral nutrition.

The addition of cysteine (as cysteine HCl) to a total parenteral nutrition (TPN) solution enhances calcium and phosphate solubility because cysteine lowers the pH of the solution. To determine whether adding cysteine to TPN solutions affected the acid-base homeostasis of infants and increased their need for acetate to obviate acidosis, we studied two groups of neonates--those receiving TPN before (group C) and after (group NC) the addition of cysteine. Measurements were made before and during the first 2 wk of TPN administration. We measured the pH of our standard TPN solution with and without the addition of cysteine. Serum carbon dioxide was significantly lower in group C despite a significantly greater intake of acetate in group NC. In the in vitro study the addition of cysteine to the TPN solution lowered the pH from 5.5 to 5.1. Newborns who received TPN solutions to which cysteine was added had lower serum carbon dioxide values and a greater need to receive acetate than did newborns who received TPN solutions without cysteine.