All Papers

Claire Wainwright, J.S. Elborn, Bonnie W. Ramsey, Gautham Marigowda et al.

BACKGROUND: Combination treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators tezacaftor (VX-661) and ivacaftor (VX-770) was designed to target the underlying cause of disease in patients with cystic fibrosis. METHODS: through week 24 (calculated as a percentage) was a key secondary end point. RESULTS: in favor of tezacaftor-ivacaftor over placebo were 4.0 percentage points and 6.8%, respectively (P<0.001 for both comparisons). The rate of pulmonary exacerbation was 35% lower in the tezacaftor-ivacaftor group than in the placebo group (P=0.005). The incidence of adverse events was similar in the two groups. Most adverse events were of mild severity (in 41.8% of patients overall) or moderate severity (in 40.9% overall), and serious adverse events were less frequent with tezacaftor-ivacaftor (12.4%) than with placebo (18.2%). A total of 2.9% of patients discontinued the assigned regimen owing to adverse events. Fewer patients in the tezacaftor-ivacaftor group than in the placebo group had respiratory adverse events, none of which led to discontinuation. CONCLUSIONS: The combination of tezacaftor and ivacaftor was efficacious and safe in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. (Funded by Vertex Pharmaceuticals; EVOLVE ClinicalTrials.gov number, NCT02347657 .).

Shiv Kumar Sarin, Ashok Choudhury, Manoj K. Sharma, Rakhi Maiwall et al.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the “APASL ACLF Research Consortium (AARC)” was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the ‘Golden Therapeutic Window’, extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.

Seema A. Bhat, Helen G. Coleman, Foad Yousef, B. T. Johnston et al.

BACKGROUND: Barrett's esophagus (BE) is a premalignant lesion that predisposes to esophageal adenocarcinoma. However, the reported incidence of esophageal adenocarcinoma in patients with BE varies widely. We examined the risk of malignant progression in patients with BE using data from the Northern Ireland Barrett's esophagus Register (NIBR), one of the largest population-based registries of BE worldwide, which includes every adult diagnosed with BE in Northern Ireland between 1993 and 2005. SUBJECTS AND METHODS: We followed 8522 patients with BE, defined as columnar lined epithelium of the esophagus with or without specialized intestinal metaplasia (SIM), until the end of 2008. Patients with incident adenocarcinomas of the esophagus or gastric cardia or with high-grade dysplasia of the esophagus were identified by matching the NIBR with the Northern Ireland Cancer Registry, and deaths were identified by matching with records from the Registrar General's Office. Incidence of cancer outcomes or high-grade dysplasia was calculated as events per 100 person-years (% per year) of follow-up, and Cox proportional hazard models were used to determine incidence by age, sex, length of BE segment, presence of SIM, macroscopic BE, or low-grade dysplasia. All P values were from two-sided tests. RESULTS: After a mean of 7.0 years of follow-up, 79 patients were diagnosed with esophageal cancer, 16 with cancer of the gastric cardia, and 36 with high-grade dysplasia. In the entire cohort, incidence of esophageal or gastric cardia cancer or high-grade dysplasia combined was 0.22% per year (95% confidence interval [CI] = 0.19% to 0.26%). SIM was found in 46.0% of patients. In patients with SIM, the combined incidence was 0.38% per year (95% CI = 0.31 to 0.46%). The risk of cancer was statistically significantly elevated in patients with vs without SIM at index biopsy (0.38% per year vs 0.07% per year; hazard ratio [HR] = 3.54, 95% CI = 2.09 to 6.00, P < .001), in men compared with women (0.28% per year vs 0.13% per year; HR = 2.11, 95% CI = 1.41 to 3.16, P < .001), and in patients with low-grade dysplasia compared with no dysplasia (1.40% per year vs 0.17% per year; HR = 5.67, 95% CI = 3.77 to 8.53, P < .001). CONCLUSION: We found the risk of malignant progression among patients with BE to be lower than previously reported, suggesting that currently recommended surveillance strategies may not be cost-effective.

Mohitosh Biswas, Shawonur Rahaman, Tapash Kumar Biswas, Zahirul Haque et al.

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Although severe acute respiratory syndrome coronavirus-2 infection is causing mortality in considerable proportion of coronavirus disease-2019 (COVID-19) patients, however, evidence for the association of sex, age, and comorbidities on the risk of mortality is not well-aggregated yet. It was aimed to assess the association of sex, age, and comorbidities with mortality in COVID-2019 patients. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Literatures were searched using different keywords in various databases. Relative risks (RRs) were calculated by RevMan software where statistical significance was set as &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.05. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; COVID-19 male patients were associated with significantly increased risk of mortality compared to females (RR 1.86: 95% confidence interval [CI] 1.67–2.07; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.00001). Patients with age ≥50 years were associated with 15.4-folds significantly increased risk of mortality compared to patients with age &amp;#x3c;50 years (RR 15.44: 95% CI 13.02–18.31; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.00001). Comorbidities were also associated with significantly increased risk of mortality; kidney disease (RR 4.90: 95% CI 3.04–7.88; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.00001), cereborovascular disease (RR 4.78; 95% CI 3.39–6.76; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.00001), cardiovascular disease (RR 3.05: 95% CI 2.20–4.25; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.00001), respiratory disease (RR 2.74: 95% CI 2.04–3.67; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.00001), diabetes (RR 1.97: 95% CI 1.48–2.64; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.00001), hypertension (RR 1.95: 95% CI 1.58–2.40; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.00001), and cancer (RR 1.89; 95% CI 1.25–2.84; &lt;i&gt;p&lt;/i&gt; = 0.002) but not liver disease (RR 1.64: 95% CI 0.82–3.28; &lt;i&gt;p&lt;/i&gt;= 0.16). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Implementation of adequate protection and interventions for COVID-19 patients in general and in particular male patients with age ≥50 years having comorbidities may significantly reduce risk of mortality associated with COVID-19.

Catherine Williamson, Victoria Geenes

In Brief Intrahepatic cholestasis of pregnancy is the most common pregnancy-specific liver disease that typically presents in the third trimester. The clinical features are maternal pruritus in the absence of a rash and deranged liver function tests, including raised serum bile acids. Intrahepatic cholestasis of pregnancy is associated with an increased risk of adverse perinatal outcomes, including spontaneous preterm delivery, meconium staining of the amniotic fluid, and stillbirth. It is commonly treated with ursodeoxycholic acid. There is accumulating evidence to suggest that intrahepatic cholestasis of pregnancy has a lasting influence on both maternal and fetal health. We review the etiology, diagnosis, and management of this intriguing condition. Intrahepatic cholestasis of pregnancy causes pruritus, deranged liver function, and raised serum bile acids and is associated with an increased risk of adverse perinatal outcomes.

Nurshad Ali

The outbreak of coronavirus disease-2019 (COVID-19) is an emerging global health threat. The healthcare workers are facing challenges in reducing the severity and mortality of COVID-19 across the world. Severe patients with COVID-19 are generally treated in the intensive care unit, while mild or non-severe patients treated in the usual isolation ward of the hospital. However, there is an emerging challenge that a small subset of mild or non-severe COVID-19 patients develops into a severe disease course. Therefore, it is important to early identify and give the treatment of this subset of patients to reduce the disease severity and improve the outcomes of COVID-19. Clinical studies demonstrated that altered levels of some blood markers might be linked with the degree of severity and mortality of patients with COVID-19.1-5 Of these clinical parameter, serum C-reactive protein (CRP) has been found as an important marker that changes significantly in severe patients with COVID-19.3 CRP is a type of protein produced by the liver that serves as an early marker of infection and inflammation.6 In blood, the normal concentration of CRP is less than 10 mg/L; however, it rises rapidly within 6 to 8 hours and gives the highest peak in 48 hours from the disease onset.7 Its half-life is about 19 hours8 and its concentration decreases when the inflammatory stages end and the patient is healing. CRP preferably binds to phosphocholine expressed highly on the surface of damaged cells.9 This binding makes active the classical complement pathway of the immune system and modulates the phagocytic activity to clear microbes and damaged cells from the organism.7 When the inflammation or tissue damage is resolved, CRP concentration falls, making it a useful marker for monitoring disease severity.7 The available studies that have determined serum concentration of CRP in patients with COVID-19 are presented in Table 1. A significant increase of CRP was found with levels on average 20 to 50 mg/L in patients with COVID-19.10, 12, 21 Elevated levels of CRP were observed up to 86% in severe COVID-19 patients.10, 11, 13 Patients with severe disease courses had a far elevated level of CRP than mild or non-severe patients. For example, a study reported that patients with more severe symptoms had on average CRP concentration of 39.4 mg/L and patients with mild symptoms CRP concentration of 18.8 mg/L.12 CRP was found at increased levels in the severe group at the initial stage than those in the mild group.1 In another study, the mean concentration of CRP was significantly higher in severe patients (46 mg/L) than non-severe patients (23 mg/L).21 The patients who died from COVID-19 had about 10 fold higher levels of CRP than the recovered patients (median 100 vs 9.6 mg/L).16 A recent study showed that about 7.7% of non-severe COVID-19 patients were progressed to severe disease courses after hospitalization,3 and compared to non-severe cases, the aggravated patients had significantly higher concentrations of CRP (median 43.8 vs 12.1 mg/L). A significant association was observed between CRP concentrations and the aggravation of non-severe patients with COVID-19 [1], and the authors proposed CRP as a suitable marker for anticipating the aggravation probability of non-severe COVID-19 patients, with an optimal threshold value of 26.9 mg/L.3 The authors also noted that the risk of developing severe events is increased by 5% for every one-unit increase in CRP concentration in patients with COVID-19. Furthermore, it was observed that patients with low oxygen saturation (SpO2 ≤ 90%) had significantly higher levels of CRP (median 76.5 mg/L) compared with patients with high oxygen saturation (SpO2 > 90%) (median 12.7 mg/L),22 indicating that more severe patients with lung damage have elevated levels of CRP. So, higher levels of CRP indicate more severe disease course-linked to lung injury and worse prognosis. CRP levels are correlated well with the severity of symptoms of patients with COVID-19; therefore, it may be a suitable marker in assessing a patient's conditions together with other clinical findings. The elevated levels of CRP might be linked to the overproduction of inflammatory cytokines in severe patients with COVID-19. Cytokines fight against the microbes but when the immune system becomes hyperactive, it can damage lung tissue. Thus, CRP production is induced by inflammatory cytokines and by tissue destruction in patients with COVID-19. In conclusion, elevated level of CRP may be a valuable early marker in predicting the possibility of disease progression in non-severe patients with COVID-19, which can help health workers to identify those patients an early stage for early treatment. Besides, COVID-19 patients with elevated levels of CRP need close monitoring and treatment even though they did not develop symptoms to meet the criteria for the severe disease course. However, CRP levels in patients with COVID-19 who may progress from non-severe to severe cases need to be further studied in large-scale multicenter studies. The authors declare that there are no conflict of interests. NA wrote and revised the manuscript.

Frederick Koster, Jack Levin, L Walker, Kenneth S. K. Tung et al.

To investigate three possible causes of the acute hemolysis in the hemolytic-uremic syndrome, we studied prospectively 207 children and 34 adults with shigellosis in Bangladesh. Nineteen children showed acute hemolytic anemia, a leukemoid reaction, thrombocytopenia and oliguria; nine other had, in addition, a serum urea nitrogen level of over 100 mg per diciliter. Eight of the nine had pseudomembranous colitis, and six of the nine died. The frequency of bacteremia was similar in all grades of shigellosis. Circulating immune complexes were found in 10 of 20 patients with uncomplicated shigellosis and in four of six with severe hemolytic-uremic syndrome. Limulus assay for endotoxemia was positive in nine of 18 patients with hemolysis (50 per cent) and three of 61 with uncomplicated shigellosis (5 per cent) (P less than 0.001). These data support the hypothesis that severe colitis in shigellosis is associated with circulating endotoxin from the colon producing coagulopathy, renal microangiopathy and hemolytic anemia.

Paul Richardson, Christopher J. Hawkey, W. A. Stack

Proton pump inhibitors (PPIs) are drugs which irreversibly inhibit proton pump (H+/K+ ATPase) function and are the most potent gastric acid-suppressing agents in clinical use. There is now a substantial body of evidence showing improved efficacy of PPIs over the histamine H2 receptor antagonists and other drugs in acid-related disorders. Omeprazole 20 mg/day, lansoprazole 30 mg/day, pantoprazole 40 mg/day or rabeprazole 20 mg/day for 2 to 4 weeks are more effective than standard doses of H2-receptor antagonists in healing duodenal and gastric ulcers. Patients with gastric ulcers should receive standard doses of PPIs as for duodenal ulcers but for a longer time period (4 to 8 weeks). There is no conclusive evidence to support the use of a particular PPI over another for either duodenal or gastric ulcer healing. For Helicobacter pylori-positive duodenal ulceration, a combination of a PPI and 2 antibacterials will eradicate H. pylori in over 90% of cases and significantly reduce ulcer recurrence. Patients with H. pylori-positive gastric ulcers should be managed similarly. PPIs also have efficacy advantages over ranitidine and misoprostol and are better tolerated than misoprostol in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In endoscopically proven gastro-oesophageal reflux disease, standard daily doses of the PPIs are more effective than H2-receptor antagonists for healing, and patients should receive a 4 to 8 week course of treatment. For severe reflux, with ulceration and/or stricture formation, a higher dose regimen (omeprazole 40 mg, lansoprazole 60 mg, pantoprazole 80 mg or rabeprazole 40 mg daily) appears to yield better healing rates. There is little evidence that PPIs lead to resolution of Barrett's oesophagus or a reduction of subsequent adenocarcinoma development, but PPIs are indicated in healing of any associated ulceration. In Zollinger-Ellison syndrome, PPIs have become the treatment of choice for the management of gastric acid hypersecretion.

Shiv Kumar Sarin, Ashok Choudhury, George Lau, Ming‐Hua Zheng et al.

Background and aims COVID-19 is a dominant pulmonary disease, with multisystem involvement, depending upon comorbidities. Its profile in patients with pre-existing chronic liver disease (CLD) is largely unknown. We studied the liver injury patterns of SARS-Cov-2 in CLD patients, with or without cirrhosis. Methods Data was collected from 13 Asian countries on patients with CLD, known or newly diagnosed, with confirmed COVID-19. Results Altogether , 228 patients [185 CLD without cirrhosis and 43 with cirrhosis] were enrolled, with comorbidities in nearly 80%. Metabolism associated fatty liver disease (113, 61%) and viral etiology (26, 60%) were common. In CLD without cirrhosis, diabetes [57.7% vs 39.7%, OR = 2.1 (1.1–3.7), p = 0.01] and in cirrhotics, obesity, [64.3% vs. 17.2%, OR = 8.1 (1.9–38.8), p = 0.002] predisposed more to liver injury than those without these . Forty three percent of CLD without cirrhosis presented as acute liver injury and 20% cirrhotics presented with either acute-on-chronic liver failure [5 (11.6%)] or acute decompensation [4 (9%)]. Liver related complications increased (p < 0.05) with stage of liver disease; a Child-Turcotte Pugh score of 9 or more at presentation predicted high mortality [AUROC 0.94, HR = 19.2 (95 CI 2.3–163.3), p < 0.001, sensitivity 85.7% and specificity 94.4%). In decompensated cirrhotics, the liver injury was progressive in 57% patients, with 43% mortality. Rising bilirubin and AST/ALT ratio predicted mortality among cirrhosis patients. Conclusions SARS-Cov-2 infection causes significant liver injury in CLD patients, decompensating one fifth of cirrhosis, and worsening the clinical status of the already decompensated. The CLD patients with diabetes and obesity are more vulnerable and should be closely monitored.

Rashidul Haque, Nasir Uddin Mollah, Ibne Karim M. Ali, Khorshed Alam et al.

A noninvasive diagnostic test for amebic liver abscess is needed, because amebic and bacterial abscesses appear identical on ultrasound or computer tomography and because it is rarely possible to identify Entamoeba histolytica in stool specimens from patients with amebic liver abscess. Here we report a method of detection in serum of circulating E. histolytica Gal/GalNAc lectin to diagnose amebic liver abscess, which was used in patients from Dhaka, Bangladesh. The TechLab E. histolytica II test (which differentiates the true pathogen E. histolytica from Entamoeba dispar) detected Gal/GalNAc lectin in the sera of 22 of 23 (96%) amebic liver abscess patients tested prior to treatment with the antiamebic drug metronidazole and 0 of 70 (0%) controls. After 1 week of treatment with metronidazole, 9 of 11 (82%) patients became serum lectin antigen negative. The sensitivity of the E. histolytica II antigen detection test for intestinal infection was also evaluated. Antigen detection identified E. histolytica infection in 50 samples from 1, 164 asymptomatic preschool children aged 2 to 5 years, including 16 of 16 (100%) culture-positive specimens. PCR analysis of stool specimens was used to confirm that most antigen-positive but culture-negative specimens were true-positive: PCR identified parasite DNA in 27 of 34 (79%) of the antigen-positive, culture-negative stool specimens. Antigen detection was a more sensitive test for infection than antilectin antibodies, which were detected in only 76 of 98 (78%) amebic liver abscess patients and in 26 of 50 (52%) patients with intestinal infection. We conclude that the TechLab E. histolytica II kit is a sensitive means to diagnose hepatic and intestinal amebiasis prior to the institution of metronidazole treatment.

Arjen M. Dondorp, Can İnce, Prakaykaew Charunwatthana, Josh Hanson et al.

BACKGROUND: This study sought to describe and quantify microcirculatory changes in the mucosal surfaces of patients with severe malaria, by direct in vivo observation using orthogonal polarization spectral (OPS) imaging. METHODS: The microcirculation in the rectal mucosa of adult patients with severe malaria was assessed by use of OPS imaging, at admission and then daily. Comparison groups comprised patients with uncomplicated falciparum malaria, patients with bacterial sepsis, and healthy individuals. RESULTS: Erythrocyte velocities were measured directly in 43 adult patients with severe falciparum malaria, of whom 20 died. Microcirculatory blood flow was markedly disturbed, with heterogeneous obstruction that was proportional to severity of disease. Blocked capillaries were found in 29 patients (67%) and were associated with concurrent hyperdynamic blood flow (erythrocyte velocity, >750 mm/s) in adjacent vessels in 27 patients (93%). The proportion of blocked capillaries correlated with the base deficit in plasma and with the concentration of lactate. Abnormalities disappeared when the patients recovered. In healthy individuals and in patients with uncomplicated malaria or sepsis, no stagnant erythrocytes were detected, and, in patients with sepsis, hyperdynamic blood flow was prominent. CONCLUSION: Patients with severe falciparum malaria show extensive microvascular obstruction that is proportional to the severity of the disease. This finding underscores the prominent role that microvascular obstruction plays in the pathophysiology of severe malaria and illustrates the fundamental difference between the microvascular pathophysiology of malaria and that of bacterial sepsis.

Masao Omata, Tatsuo Kanda, Lai Wei, Ming‐Lung Yu et al.

The Asian-Pacific Association for the Study of the Liver (APASL) convened an international working party on the "APASL consensus statements and recommendation on management of hepatitis C" in March, 2015, in order to revise "APASL consensus statements and management algorithms for hepatitis C virus infection (Hepatol Int 6:409-435, 2012)". The working party consisted of expert hepatologists from the Asian-Pacific region gathered at Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed and debated to draft a revision. Participants of the consensus meeting assessed the quality of cited studies. Finalized recommendations on treatment of hepatitis C are presented in this review.

Mark Zeller, Mustafizur Rahman, Elisabeth Heylen, Sarah De Coster et al.

Rotarix™ was introduced into the Belgian market in 2006 and RotaTeq™ in 2007, quickly reaching more than 85% vaccine coverage of all newborns in Belgium. The incidence of rotavirus gastroenteritis has been monitored in the Gasthuisberg University Hospital (GUH), Belgium since 1986, and since 1999 the genotypes of circulating rotavirus strains have been determined. The average percentage of rotavirus positive cases out of all hospitalized gastro-enteritis cases tested (>95% of these cases are younger than 5 years old) at the GUH between 1986 and 2006 was 19.0%. This percentage dropped to 12.4%, 9.6% and 6.4% in the three seasons post vaccine introduction (2006-2009), which is a decline of 34.7%, 49.4% and 66.3% respectively. In addition the rotavirus season was found to be shortened and delayed. The prevalence of the G2 genotype sharply increased in the 2006-2007 rotavirus season compared to the previous seasons and remained high (30-40%) in the 2007-2008 and 2008-2009 seasons. Rotavirus vaccines have strongly reduced the number of children hospitalized due to a rotavirus infection at the GUH; it is however unclear if the predominance of G2 genotypes is related to the vaccine introduction, or if this is attributable to normal genotype fluctuations. Continued surveillance will be pivotal to answer this question in the future.

APASL ACLF Working Party, Ashok Choudhury, Ankur Jindal, Rakhi Maiwall et al.

Background and aims Acute-on-chronic liver failure (ACLF) is a progressive disease associated with rapid clinical worsening and high mortality. Early prediction of mortality and intervention can improve patient outcomes. We aimed to develop a dynamic prognostic model and compare it with the existing models. Methods A total of 1402 ACLF patients, enrolled in the APASL-ACLF Research Consortium (AARC) with 90-day follow-up, were analyzed. An ACLF score was developed in a derivation cohort (n = 480) and was validated (n = 922). Results The overall survival of ACLF patients at 28 days was 51.7%, with a median of 26.3 days. Five baseline variables, total bilirubin, creatinine, serum lactate, INR and hepatic encephalopathy, were found to be independent predictors of mortality, with AUROC in derivation and validation cohorts being 0.80 and 0.78, respectively. AARC-ACLF score (range 5-15) was found to be superior to MELD and CLIF SOFA scores in predicting mortality with an AUROC of 0.80. The point scores were categorized into grades of liver failure (Gr I: 5-7; II: 8-10; and III: 11-15 points) with 28-day cumulative mortalities of 12.7, 44.5 and 85.9%, respectively. The mortality risk could be dynamically calculated as, with each unit increase in AARC-ACLF score above 10, the risk increased by 20%. A score of ≥11 at baseline or persisting in the first week was often seen among nonsurvivors (p = 0.001). Conclusions The AARC-ACLF score is easy to use, dynamic and reliable, and superior to the existing prediction models. It can reliably predict the need for interventions, such as liver transplant, within the first week.

John P. Clancy, Lieven Dupont, Michael W. Konstan, Joanne Billings et al.

RATIONALE: Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. OBJECTIVES: To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. METHODS: 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R). RESULTS: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs -0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). CONCLUSIONS: Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

Golam Rabbani, Thomas Butler, Joseph A. Knight, S. C. Sanyal et al.

To evaluate the antisecretory activity of berberine sulfate (BS), we studied 165 adult patients with acute diarrhea due to enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae in randomized controlled trials. In patients with ETEC diarrhea who received 400 mg of BS in a single oral dose, the mean stool volumes were significantly less than those of the controls during three consecutive 8-hr periods after treatment (P less than .05). At 24 hr after treatment, significantly more patients who were treated with BS and had ETEC diarrhea stopped having diarrhea as compared with the controls (42% vs 20%, P less than .05). In patients with cholera who received 400 mg of BS, the mean 8-hr stool volume during the second 8-hr period after treatment declined to 2.22 liters, which was significantly less than the 2.79 liters found in the controls (P less than .05). However, patients with cholera who received 1200 mg of BS plus tetracycline did not have significant reduction in stool output compared with patients who received tetracycline alone. No side effects of BS were noted. These results indicated that BS is an effective and safe antisecretory drug for ETEC diarrhea, whereas the activity against cholera is slight and not additive with tetracycline.

Habibul Ahsan, Yu Chen, Muhammad G. Kibriya, Vesna Slavkovich et al.

We conducted a case-control study to investigate interindividual variability in susceptibility to health effects of inorganic arsenic due to arsenic metabolism efficiency, genetic factors, and their interaction. A total of 594 cases of arsenic-induced skin lesions and 1,041 controls was selected from baseline participants in a large prospective cohort study in Bangladesh. Adjusted odds ratios (OR) for skin lesions were estimated in relation to the polymorphisms in the glutathione S-transferase omega1 and methylenetetrahydrofolate reductase genes, the percentage of monomethylarsonous acid (%MMA) and dimethylarsinic acid (%DMA) in urine, and the ratios of MMA to inorganic arsenic and DMA to MMA. Water arsenic concentration was positively associated with %MMA and inversely associated with %DMA. The dose-response relationship of risk of skin lesion with %MMA was more apparent than those with other methylation indices; the ORs for skin lesions in relation to increasing %MMA quartiles were 1.00 (reference), 1.33 [95% confidence interval (95% CI), 0.92-1.93], 1.68 (95% CI, 1.17-2.42), and 1.57 (95% CI, 1.10-2.26; P for trend = 0.01). The ORs for skin lesions in relation to the methylenetetrahydrofolate reductase 677TT/1298AA and 677CT/1298AA diplotypes (compared with 677CC/1298CC diplotype) were 1.66 (95% CI, 1.00-2.77) and 1.77 (95% CI, 0.61-5.14), respectively. The OR for skin lesions in relation to the glutathione S-transferase omega1 diplotype containing all at-risk alleles was 3.91 (95% CI, 1.03-14.79). Analysis of joint effects of genotypes/diplotypes with water arsenic concentration and urinary %MMA suggests additivity of these factors. The findings suggest that arsenic metabolism, particularly the conversion of MMA to DMA, may be saturable and that differences in urinary arsenic metabolites, genetic factors related to arsenic metabolism, and their joint distributions modulate arsenic toxicity.

Lesley Bailie, Maurice B. Loughrey, Helen G. Coleman

Background & aims Certain subsets of colorectal serrated polyps (SP) have malignant potential. We performed a systematic review and meta-analysis to investigate the association between modifiable lifestyle factors and risk for SPs. Methods We conducted a systematic search of Medline, Embase, and Web of Science for observational or interventional studies that contained the terms risk or risk factor, and serrated or hyperplastic, and polyps or adenomas, and colorectal (or synonymous terms), published by March 2016. Titles and abstracts of identified articles were independently reviewed by at least 2 reviewers. Adjusted relative risk (RR) and 95% confidence interval (CI) were combined using random effects meta-analyses to assess the risk of SP, when possible. Results We identified 43 studies of SP risk associated with 7 different lifestyle factors: smoking, alcohol, body fatness, diet, physical activity, medication, and hormone-replacement therapy. When we compared the highest and lowest categories of exposure, factors we found to significantly increase risk for SP included tobacco smoking (RR, 2.47; 95% CI, 2.12-2.87), alcohol intake (RR, 1.33; 95% CI, 1.17-1.52), body mass index (RR, 1.40; 95% CI, 1.22-1.61), and high intake of fat or meat. Direct associations for smoking and alcohol, but not body fat, tended to be stronger for sessile serrated adenomas/polyps than hyperplastic polyps. In contrast, factors we found to significantly decrease risks for SP included use of nonsteroidal anti-inflammatory drugs (RR, 0.77; 95% CI, 0.65-0.92) or aspirin (RR, 0.81; 95% CI, 0.67-0.99), as well as high intake of folate, calcium, or fiber. No significant associations were detected between SP risk and physical activity or hormone replacement therapy. Conclusions Several lifestyle factors, most notably smoking and alcohol, are associated with SP risk. These findings enhance our understanding of mechanisms of SP development and indicate that risk of serrated pathway colorectal neoplasms could be reduced with lifestyle changes.

Verena Bihrer, Mireen Friedrich‐Rust, Bernd Kronenberger, Nicole Forestier et al.

OBJECTIVES: The liver contains large amounts of microRNA-122 (miR-122), whereas other tissues contain only marginal amounts of this miRNA. MicroRNAs have also been found to circulate in the blood in a cell-free form; their potential as readily accessible disease markers is currently evaluated. Here, we investigated if the serum levels of miR-122 might be useful as disease parameter in patients with chronic hepatitis C virus (HCV) infection. METHODS: RNA was extracted from sera of patients with chronic HCV infection (CHC) and healthy controls and was analyzed for miR-22 content by quantitative real-time reverse-transcription polymerase chain reaction. miR-122 serum levels were correlated with standard parameters of liver function. Liver biopsies from the same patients were examined for the histologic activity index (HAI) and the degree of fibrosis. RESULTS: Sera from patients with CHC contained higher levels of miR-122 than sera from healthy controls. Serum miR-122 levels correlated well with markers of liver inflammatory activity, that is, the serum levels of alanine leucine transaminase (ALT) and aspartate transaminase, and the HAI score. In patients with persistently normal ALT levels, serum miR-122 levels did not differ from healthy controls. There was no correlation of serum miR-122 levels with serum albumin, international normalized ratio, liver fibrosis, or serum HCV RNA. CONCLUSIONS: The serum level of miR-122 strongly correlates with serum ALT activity and with necroinflammatory activity in patients with CHC and elevated ALT levels, but not with fibrosis stage and functional capacity of the liver.