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Background & Aims: Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB., Method: This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 μg BRII-179 (Part 1, n = 25) and 40 μg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored., Results: Both 20 μg and 40 μg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment., Conclusion: In patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies., Clinical Trial Number: ACTRN12619001210167., Lay Summary: BRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic., Competing Interests: Ji Y, Li D, Zhang Y, Hamatake R, Li C, Li Y, and Zhu Q: Employees of and hold stock and options in Brii Biosciences. Ahmed T, Anderson D: Employees of and hold stock in VBI Vaccines, which own an interest in BRII-179. Lim TH: Data Safety Monitoring Board or Advisory Board: Brii Biosciences (BRII-179-001 study). Yoon JH: Grants: AstraZeneca, Daewoong Pharmaceuticals, Hanmi Pharmaceuticals. Lim Y: Grants/Consultant/Payments: Gilead Sciences; Data Safety Monitoring Board or Advisory Board: Gilead Sciences, Vaccitech. Strasser S: Payment or honoraria: AbbVie, Gilead, MSD, Eisai, Ipsen, AstraZeneca, BMS, Roche, Guebert; Data Safety Monitoring Board or Advisory Board: AbbVie, CSL Behring, MSD, AstraZeneca, Roche, Eisai, Bayer, Ipsen, Norgine, Novartis. Yuen M: Grants: Assembly Biosciences, Arrowhead Pharmaceuticals, Bristol Myers Squibb, Fujirebio Incorporation, Gilead Sciences, Merck Sharp and Dohme, Springbank Pharmaceuticals, Roche; Consultant: AbbVie, Aligos Therapeutics, Arbutus Biopharma, Bristol Myer Squibb, Dicerna Pharmaceuticals, Finch Therapeutics, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals, Roche; Payment or honoraria: Arbutus Biopharma, Bristol Myer Squibb, Discerna Pharmaceuticals, Fujirebio Incorporation, Gilead Sciences. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

A 59-year-old man with refractory Cronkhite-Canada syndrome (CCS) had poor clinical response to high-dose intravenous steroids, azathioprine, total parenteral nutrition and best supportive care. He remained highly symptomatic with abdominal pain, diarrhoea, recurrent sepsis and profound weight loss. Infliximab induction was given as rescue therapy, with marked clinical improvement observed within 3 weeks. This allowed steroid taper. Within 12 months of infliximab therapy, he achieved complete clinical remission and returned to his baseline weight and a full oral diet. Sequential endoscopies observed significant regression of previous marked gastrointestinal polyposis, including histological remission on colonic biopsies at 3.5 and 5 years of treatment. He currently remains in remission following 6 years of combination therapy with 5 mg/kg 8 weekly infliximab and azathioprine, and there is ongoing discussion with regard to the benefits and risks of therapy de-escalation. This case demonstrates the effectiveness of infliximab in inducing and maintaining remission in refractory CCS., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: To compare the efficacy of a descalating dose of interferon (48 weeks) versus a combination therapy of interferon and ribavirin (24 weeks) in hepatitis C positive subjects who relapsed within six months of cessation of a standard six month course of interferon three million units thrice weekly., Methods: All 32 subjects had biopsy proven chronic hepatitis C, were PCR positive and had elevated transaminase enzymes at least one and a half times the upper limit of normal. Subjects were randomly assigned to either a descalating dose of interferon-alpha-2a; six million units thrice weekly for 24 weeks followed by 3 MIU 3x for 24 weeks or interferon three million units thrice weekly for 24 weeks plus ribavirin 1,000 mg/day for 12 weeks. A complete virological response was defined as a negative PCR for HCV RNA at 24 weeks after cessation of therapy., Results: Sixteen patients were assigned to each arm and the sustained virological response was 50% for both the interferon and combination therapy arm (pNS). The biochemical response correlated with the virological response; 7/8 virological responders in the interferon alone had normalisation of transaminase 24 weeks post treatment as did 8/8 of those in the combination arm. One patient withdrew from treatment in the descalating interferon group and three required dose reduction. No subjects in the combination arm discontinued therapy but dose reduction was required in three subjects., Conclusion: High dose descalating interferon-alpha 2a and a combination of interferon-alpha 2a and ribavirin were effective in achieving a sustained virological response in 50% of subjects who had relapsed after a standard six month course of interferon.

Aims: To describe the prevalence and severity of dyspepsia and gastro-oesophageal reflux in the community, to investigate their association with lifestyle factors and to evaluate the consultation pattern for these conditions., Method: A previously validated questionnaire was posted to 1000 adults randomly selected from the electoral rolls of the greater Wellington region. It investigated symptoms of dyspepsia, reflux, lifestyle and consultation pattern over the previous twelve months., Results: Response rate was 81.7%. Prevalence of dyspepsia was 34.2%. Prevalence of reflux was 30%. The overall prevalence of both symptom groups combined was 45.2%. Most subjects had multiple symptoms. Results indicated 63% of subjects with reflux also had symptoms of dyspepsia and 56% of subjects with dyspepsia showed symptoms of reflux. Although 69% of subjects with heartburn used over-the-counter medications, only 17% consulted medical practitioners. Current and ex-smokers had a higher prevalence of reflux. Dyspeptic symptoms were not associated with alcohol intake or aspirin use. Prevalence of dyspeptic symptoms did not change with increasing age., Conclusions: Dyspepsia is very common in the community. Significant overlap among the subgroups of dyspepsia makes a classification, based on symptoms alone, of questionable value. Frequency and severity of symptoms should be incorporated in the definition to exclude those subjects with trivial symptoms.

Background: There is not at present a suitable disease-specific health-related quality of life instrument for uninvestigated dyspepsia and functional (non-ulcer) dyspepsia., Aim: To develop a new multi-dimensional disease-specific instrument., Methods: The Nepean Dyspepsia Index (NDI) was designed to measure impairment of a subject's ability to engage in relevant aspects of their life and also their enjoyment of these aspects; in addition, the individual importance of each aspect is assessed. A 42-item quality of life measure was developed and tested, both in out-patients presenting to general practice with upper gastrointestinal complaints (n = 113) and in a randomly chosen population-based sample (n = 347)., Results: Adequate face and content validity was documented by an expert panel. Factor analysis identified four clinically relevant subscales: interference with activities of daily living, work, enjoyment of life and emotional well-being; lack of knowledge and control over the illness; disturbance to eating or drinking; and disturbance to sleep because of dyspepsia. These scales had high internal consistency. Both symptoms and the quality of life scores discriminated dyspepsia from health., Conclusion: The Nepean Dyspepsia Index is a reliable and valid disease-specific index for dyspepsia, measuring symptoms and health-related quality of life.

Two hundred and forty-three patients receiving renal replacement therapy (RRT) and 20 renal unit staff were tested for antibodies to hepatitis C (HCV). Three patients (1.2%) were positive by the first generation test kit, the lowest rate in patients receiving RRT reported in the literature to date. These three, and eight other patients tested positive by the second generation kit, a prevalence rate of 4.5%. Anti-HCV antibody positivity was associated with higher mean serum alanine aminotransferase (p = 0.0003) and aspartate aminotransferase (p = 0.018) levels. However, only one of the 11 anti-HCV positive patients had liver transaminase levels more than twice the upper limit of the laboratory reference range. Anti-HCV positivity was associated with a higher mean number of units of blood transfused (p = 0.035). None of 20 staff were anti-HCV positive. Twenty-five of 212 (11.7%) patients reported a history of liver disease; none of these were anti-HCV positive. Hepatitis B surface antigen was detected in eight of 215 (3.7%) patients, of which three were e antigen positive. There was evidence of past hepatitis B infection in 53 of 215 (24.7%) patients, more frequently in Maoris (p = 0.001). Overall, significantly raised liver transaminases were present in three of 198 (1.5%) patients and in no staff. This unit has a remarkably low prevalence of antibodies to HCV, an observation supported by the low rate of abnormal serum liver enzymes.

The usefulness of the serum aspartate aminotransferase (AST): serum alanine aminotransferase (ALT) ratio as a guide to the presence of alcoholism was evaluated in four groups of patients. In alcoholics with elevated transaminases the mean AST:ALT ratio was found to be 1.50 (95% confidence interval (CI): 1.49-1.51), in hepatitis B infection 0.51 (95% CI: 0.50-0.52), in liver cancer 1.25 (95% CI: 1.20-1.29), and in nonmalignant obstructive jaundice 0.59 (95% CI: 0.57-0.61). In alcoholics with normal transaminases the AST:ALT ratio was 1.64 (95% CI: 1.61-1.67). The combination of an AST:ALT ratio of greater than 1.00 with an erythrocyte mean cell volume (MCV) above 90.0 fL resulted in a sensitivity of 97.3% and a specificity of 88.9% for detecting alcoholism in these four groups of patients.

The effect of chronic alcohol abuse on the secretion of pancreatic exocrine proteins was studied. Pure pancreatic juice (PPJ) was obtained by endoscopic cannulation of the pancreatic duct from 21 healthy, nonalcoholic volunteers and 25 chronic alcoholics. Peak concentration and output of total proteins after sequential stimulation with secretin and cholecystokinin was elevated significantly in chronic alcoholics when compared to nonalcoholic subjects. The most striking change in the secretory proteins investigated was exhibited by the trypsinogens. Although the concentrations of all three trypsinogen variants were elevated significantly in PPJ of chronic alcoholics, most of the increase resulted from an approximately fivefold increase of the anionic variant, suggesting nonparallel alterations in the synthesis of pancreatic exocrine proteins. Whereas the ratio of cationic-anionic trypsinogen in the control group was consistently greater than one, it was, without exception, below one in the chronic alcoholics group. As there was no significant increase in trypsin inhibitor in PPJ of alcoholics, the ratio of trypsinogen-trypsin inhibitor showed a highly significant increase in this group. This distortion of the normal ratio in favor of trypsinogen may facilitate premature activation of pancreatic zymogens as postulated in acute pancreatitis. The concentrations of other zymogens and lysosomal hydrolases in PPJ of chronic alcoholics showed small, but not significant, increases, with the exception of leucine naphthylamidase which was significantly elevated. Nonparallel secretion of some exocrine proteins previously described in healthy nonalcoholic subjects was affected selectively by chronic ethanol ingestion. Thus, in chronic alcoholics the secretory kinetics of trypsinogen and chymotrypsinogen were altered, but trypsin inhibitor secretion remained apparently unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of the study was to investigate the specificity of psychological profiles in female Irritable Bowel Syndrome (IBS) patients by a comparison with a gastrointestinal patient control group and with a normal population control group. The results showed that the IBS patients scored significantly higher than the normal population sample on three test scales: Anxiety, Phobic and Somatisation. Our results thus support the conclusion of earlier authors that a moderate degree of psychoneurotic disorder exists amongst IBS patients. However, the patient control group also scored significantly higher than the normal control group on two factors (Phobic and Somatisation), and the comparison between the IBS group and the patient control group did not reveal any significant differences. It is suggested that attention to the psychological needs of both IBS and other gastrointestinal disease patients should form an important part of the management strategy, particularly in the former--where a consistently clear benefit for any particular therapy has yet to be shown.

The cellular mechanisms controlling adaptive intestinal mucosal hypo- and hyperplasia are poorly understood but changes in tissue polyamine levels and in the activity of the key enzymes controlling their synthesis (ornithine decarboxylase: ODC) and degradation (diamine oxidase: DAO) have been implicated. Therefore, in two models of adaptive mucosal hyperplasia (pancreatico-biliary diversion, PBD, achieved by surgically transposing the jejunum to lie between pylorus and ampulla of Vater, and 90% small bowel resection, SBR-both studied 8 weeks after surgery) and in one model of hypoplasia (8 days total parenteral nutrition) we measured indices of mucosal mass (wet weight, protein and DNA per 10-cm intestine), the growth-associated polyamines (putrescine, spermidine and spermine per 10-cm intestine and per mg DNA) and DAO activity in the duodenum, five 10-cm segments of jejunum, five 10-cm segments of ileum and in the colon, and compared the results with those found in transected or unoperated controls. The results for the indices of mucosal mass confirmed that TPN led to a modest degree of small bowel mucosal hypoplasia whilst PBD, and particularly 90% SBR, stimulated marked adaptive hyperplasia. There were corresponding changes in the amounts of putrescine and spermidine (but not of spermine)-not only when the results were expressed per unit length but also when calculated per mg mucosal DNA and in the ratio of spermidine:spermine. There was an increasing proximal-to-distal gradient in mucosal DAO per unit length intestine in all experimental groups but when the results were expressed per mg DNA, the ileal DAO levels were significantly reduced in the PBD and resection groups, when compared with the controls. These data support the hypothesis that polyamines play a major, and perhaps a controlling, role in regulating adaptive intestinal mucosal growth.

Pancreatic secretory profiles for 11 pancreatic enzymes and proteins were established in nine patients with cancer of the pancreas by analysis of minute-to-minute collections of pure pancreatic juice after sequential administration of secretin and cholecystokinin. Aspiration of pancreatic fluid sufficient for this study was successful in less than one quarter of the patients investigated because of ductal obstruction and/or the effect of the disease on pancreatic exocrine function. Flow rates in patients generally were lower than in healthy individuals, and secretion of total protein, trypsin inhibitor, and activity of digestive enzymes were in the lowest part of or below the normal range. Normal flow rates in four patients precluded ductal obstruction as the sole cause of impaired enzyme secretion. Activity of lysosomal hydrolases in pancreatic juice of these patients, in contrast to that of digestive enzymes, remained within or rose above the normal range. The tumor appeared to have a diametrically opposite effect on the two different groups of enzymes. This is illustrated most dramatically in the form of ratios of lysosomal to digestive enzymes. Virtually all of 10 such ratios were far above the normal average in all patients, and none was below. In an analogous investigation of 25 patients with chronic pancreatitis only three exhibited the ratio pattern characteristic of pancreatic cancer patients. Pancreatic secretory profiles appear to be capable of discriminating between cancer of the pancreas and chronic pancreatitis in a high percentage of cases. Extension and refinement of this approach may facilitate early detection of cancer of the pancreas.

The polyamines, putrescine, spermidine, and spermine, are believed to play an important role in modulating normal and adaptive intestinal mucosal growth. Polyamine synthesis is rate limited by ornithine decarboxylase (ODC) and ODC activity is specifically inhibited by -difluoromethyl ornithine (DFMO). To assess the importance of polyamines in adaptive growth we first measured mucosal polyamine profiles at different sites in the normal rat intestine and compared the results with those obtained in adaptive hypoplasia (seven days parental nutrition, TPN), in the adaptive hyperplasia of two weeks after 90% small bowel resection (SBR) or pancreatico biliary diversion (PBD). We then examined the effects of DFMO (2% in drinking water, daily from two days before surgery) on the polyamine concentrations and the adaptive response to PBD. The hyperplasia of SBR and PBD was associated with increases in all the polyamine concentrations particularly putrescine. TPN induced a modest degree of hypoplasia and little change in polyamine synthesis resulting in subnormal polyamine concentrations and significantly inhibited the mucosal adaptive response. Changes in polyamine metabolism are important in intestinal mucosal adaptation and by controlling these changes adaptive growth can be controlled.

A model for spontaneous tumour formation in the rat pancreas is described that requires neither cocarcinogens nor dietary manipulation. Short term hypercholecystokininaemia, when induced by raw soya flour feeding, induces benign and malignant tumours of the rat pancreas. Pancreaticobiliary diversion (PBD) results in hypercholecystokininaemia and in the short term, pancreatic hyperplasia. Longterm PBD was done to establish whether hypercholecystokininaemia thus produced would also lead to pancreatic neoplasia. After a period of 16-21 months hyperplastic and adenomatous nodules, one of the latter showing carcinoma in situ, were found in PBD rats but not in sham operated control rats.

Clinical details of 30 Caucasian women suffering from the irritable bowel syndrome were analyzed. Dietary fiber intakes, stool transit time, and stool weights were compared between groups of differing bowel habit and no statistically significant differences were found. A significant correlation between the clinical severity and the anxiety score on the Middlesex Hospital Questionnaire was present, but there was no correlation with other psychoneurotic traits or self-rating depression scores. Two to 3-year follow-up after management with a high fiber diet in 14 patients, showed that symptoms had improved greatly in seven, were unchanged in five, and were worse in two. Although dietary fiber had increased by a mean of 6.7 g/day, the clinical course could not be correlated with the amount of fiber consumed nor was it possible to predict the course of the individual patient from any clinical or psychological score. Despite persistence of symptoms at follow-up these were generally less severe and associated with significant decreases in anxiety, somatic and self-rating depression scores with the somatic score correlating with a decrease in clinical severity.

The evidence for and against an enteropancreatic trophic axis is reviewed. Luminal nutrition is essential for the maintenance of normal intestinal mucosal, and exocrine pancreatic, structure and function. Exclusion of luminal nutrition leads to mucosal hypoplasia and hypofunction with similar changes in the pancreas. The trophic effect of luminal nutrition may be mediated through the release of regulatory peptides with endocrine or paracrine effects. Enteroglucagon is the strongest candidate for the role of 'enterotrophin' while cholecystokinin (CCK) markedly influences pancreatic growth. Thus, CCK not only stimulates exocrine pancreatic secretion but makes acinar cells divide and the pancreas grow. The cellular mechanisms whereby trophic peptides influence normal and adaptive growth are also discussed with emphasis on polyamines (putrescine, spermidine and spermine) and the key enzymes controlling their synthesis (ornithine decarboxylase; ODC) and degradation (diamine oxidase; DAO). When polyamine synthesis is blocked with the ODC inhibitor, difluoromethyl ornithine (DFMO), the adaptive intestinal hyperplasia of pancreatico-biliary diversion is either inhibited or completely prevented. A proposed sequence of events might be as follows: luminal nutrients, particularly long-chain fats, reach the ileum and colon and stimulate increased enteroglucagon release. Enteroglucagon binds to cell receptors and triggers an intracellular cascade involving ODC and the polyamines, which, in turn, stimulate RNA polymerase, DNA, RNA and protein synthesis, cell division, and adaptive tissue growth.

The prevalence with which alcoholic pancreatitis is associated with alcoholic liver disease is unclear. To investigate this association further, we have reviewed the autopsy findings of 1022 patients who died from alcoholic liver disease and compared these findings with those from 352 patients who died from cardiac or pulmonary disease. All patients who died from liver disease had a history of chronic alcoholism with clinical and biochemical evidence of severe liver damage. Death resulted from hepatic coma, gastrointestinal bleeding, or infection. Liver disease patients were classified into two groups: (1) those with cirrhosis (77%) and (2) those without cirrhosis but with acute and/or chronic sclerosing hyaline necrosis (23%). Anatomic and histopathologic changes characteristic of chronic pancreatitis were found in 203 patients in approximately the same frequency (20% and 18%, respectively) in both groups. Acute pancreatitis without chronic lesions was observed in 8% and 10% of both groups, respectively. In the control group of 352 autopsies (122 cardiac and 230 pulmonary patients), the overall prevalence of pancreatitis, at 2.6%, was significantly (P less than 0.001) lower than that observed in the alcoholic liver disease groups. A total of 22 cases (50%) dying from acute or chronic sclerosing hyaline necrosis had severe chronic calcifying pancreatitis compared to 29 patients (18%) (P less than 0.001) dying from cirrhosis. By contrast, dense fibrosis was significantly (P less than 0.001) more commonly observed in patients with cirrhosis. We conclude that pancreatitis occurs frequently in patients dying from alcoholic liver disease but is an uncommon finding in patients dying from other causes.(ABSTRACT TRUNCATED AT 250 WORDS)

One hundred randomly selected inpatients were examined with both double-contrast barium meal and endoscopy in a blinded prospective fashion. All studies were done by staff personnel, with equal clinical information available to both the radiologist and endoscopist. The final diagnosis was made by a review committee of participating radiologists and endoscopists. Endoscopy was more sensitive (92% versus 54%, p less than 0.001) and specific (100% versus 91%, p less than 0.05) than the double-contrast barium meal. Both procedures significantly affected the clinical outcome of the patient, the effect of endoscopy being significantly greater than that of the double-contrast barium meal. Although errors with the barium study related predominantly to an inability to show subtle lesions, poor patient cooperation and perceptual and technical failures were additional significant factors. Endoscopy is recommended for certain groups of patients.

Sixty-nine patients with symptomatic and endoscopically diagnosed gastric or duodenal ulcers received treatment with either pirenzepine 100 mg or cimetidine 800 mg one hour before bedtime in a prospective randomised, double blind study. Fifty-five patients completed the six weeks treatment period of whom 13/15 (87%) gastric ulcers and 13/16 (81%) duodenal ulcers, healed with pirenzepine compared to 8/11 (73%) gastric ulcers and 10/13 (77%) duodenal ulcers treated with cimetidine for the same period. The differences in healing rates between pirenzepine and cimetidine were not statistically significant. Pirenzepine 100 mg administered at night is therefore an effective treatment for gastric and duodenal ulcers.