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Background: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies., Methods: PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228)., Findings: Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight)., Interpretation: Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease., Funding: Wellcome and PredictImmune Ltd., Competing Interests: Declaration of interests NMN reports personal fees from Galapagos, Janssen, Lilly, SBK Healthcare, and Takeda outside the submitted work; and grants from Dr Falk, Pfizer, Pharmacosmos, and Tillotts Pharma outside the submitted work. JCL reports consultancy fees from AbbVie, AgPlus Diagnostics, PredictImmune, and C4X Discover outside the submitted work; and grants from GSK outside the submitted work. KVP reports personal fees from AbbVie, DrFalk, Galapagos, Janssen, PredictImmune, Pfizer, and Takeda outside the submitted work; grants from AbbVie, Celltrion, Dr Falk, Ferring, Janssen, Takeda, and Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Galapagos, Janssen, and Pfizer outside the submitted work. TA reports personal fees from Amgen, Celltrion, Janssen, Lilly, Pfizer, and Tillotts Pharma; and grants from Biogen, Celltrion, Galapagos, Nova Pharmaceuticals, Pfizer, Roche, and Takeda outside the submitted work. JWB reports personal fees from Janssen outside the submitted work. RC reports personal fees from AbbVie, Galapagos, and Lilly outside the submitted work, grants from Celltrion, Ferring, and Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie and Bristol Myers Squibb outside the submitted work. SD reports personal fees from AbbVie, Ferring, Janssen, and Takeda outside the submitted work; grants from AbbVie, Dr Falk, and Janssen, outside the submitted work; and fees from advisory board membership of AbbVie outside the submitted work. DD reports personal fees from Takeda outside the submitted work; and grants from AbbVie and Janssen outside the submitted work. PMI reports personal fees from AbbVie, Arena, Boehringer-Ingelheim, BMS, Celgene, Celltrion, Dr Falk, Galapagos, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Prometheus, Sandoz, Samsung Bioepis, Sapphire Medical, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott outside the submitted work; and grants from AbbVie and Takeda outside the submitted work. AJK reports personal fees from AbbVie, Galapagos, and Takeda outside the submitted work; grants from AbbVie, Janssen, and Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie and Janssen outside the submitted work. CM reports grants from Janssen outside the submitted work. CSP reports personal fees from Dr Falk outside the submitted work. TR reports personal fees from AbbVie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Novartis, Numab, Janssen, Pfizer, Roche, Takeda, UCB, and XAP therapeutics outside the submitted work; grants from AbbVie outside the submitted work; and fees from data monitoring board membership of UCB outside the submitted work. SS reports personal fees from AbbVie, Celltrion, Dr Falk, Ipsen, Janssen, and Takeda outside the submitted work. HRTW reports fees from advisory board membership of Pfizer outside the submitted work. SV reports personal fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Surrozen, Takeda, Theravance, Tillotts Pharma, VectivBio, Ventyx, and Zealand Pharma outside the submitted work; and grants from AbbVie, Galapagos, J&J, Pfizer, and Takeda outside the submitted work. VJ reports personal fees from AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, BMS, Celltrion, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead, Innomar, JAMP, Janssen, Lilly, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Roivant, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, Topivert, Ventyx, and Vividion outside the submitted work; and fees from advisory board membership of AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, BMS, Celltrion, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead, Innomar, JAMP, Janssen, Lilly, Merck, Metacran, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, Topivert, Ventyx, and Vividion outside the submitted work. GRDH reports personal fees from AbbVie, Alimentiv, AstraZeneca, Immunic, J&J, Lilly, Pfizer, Takeda, Tillotts, and Ventyx outside the submitted work; grants from AbbVie, BMS, Lilly, Pfizer, and Takeda outside the submitted work; and fees from advisory board membership of AstraZeneca, Galapagos, and Seres Health outside the submitted work. EFM reports being a co-founder and receiving consultancy fees from PredictImmune; and holds PredictImmune stock or stock options. PAL reports being a co-founder and receiving consultancy fees from PredictImmune; and holds PredictImmune stock or stock options. JOL reports personal fees from AbbVie, Atlantic Healthcare, Bristol Meyer Squibb, Celgene, Celltrion, Engytix, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Norgine, Pfizer, Shire, and Takeda outside the submitted work; and grants from AbbVie, Ferring, Gilead, Takeda, and Shire outside the submitted work. NAK reports personal fees from Amgen, Bristol Myers Squibb, Celltrion, Falk, Galapagos, Janssen, Pfizer, Pharmacosmos, Takeda, and Tillotts Pharma outside the submitted work; and reports data monitoring board membership for the BEACON study outside the submitted work. KGCS reports being a co-founder and receiving consultancy fees from Predictimmune; consultancy fees from GSK outside the submitted work; and holds PredictImmune stock or stock options. MP reports personal fees from Janssen and Takeda outside the submitted work; and grants from AstraZeneca, Galapagos, Gilead, and Pfizer outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Pompe disease (PD) is a rare, autosomal-recessively inherited deficiency in the enzyme acid α-glucosidase. It is a spectrum disorder; age at symptom onset and rate of deterioration can vary considerably. In affected infants prognosis is poor, such that without treatment most infants die within the first year of life. To lose a baby in their first year of life to a rare disease causes much regret, guilt, and loneliness to parents, family, and friends. To lose a baby needlessly when there is an effective treatment amplifies this sadness. With so little experience of rare disease in the community, once a baby transfers to their home they are subject to a very uncertain and unyielding diagnostic journey while their symptomology progresses and their health deteriorates. With a rare disease like PD, the best opportunity to diagnose a baby is at birth. PD is not yet included in the current newborn screening (NBS) panel in Australia. Should it be? In late 2018 the Australian Pompe Association applied to the Australian Standing committee on Newborn Screening to have PD included. The application was not upheld. Here we provide an overview of the rationale for NBS, drawing on the scientific literature and perspectives from The Australian Pompe Association, its patients and their families. In doing so, we hope to bring a new voice to this very important debate., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (© 2020 by the authors.)

The Pompe model is the term used by the Pompe community to describe the relationship that exists between the patient community, the medical/scientific community, and industry. The development of the Pompe model represented a new paradigm for the involvement of patients in new treatments-and also for scientists and pharmaceutical companies. It saw patients developing a sense of agency, of involvement in the process of treatment development rather than powerless recipients or (if lucky) occasional spectators. At the same time, as described below, it benefited the other partners in the process with the result that the different components of the model added up to more than the sum of their parts. However, in order for this to happen, each part had to undergo a transformation in mindset. The development of enzyme replacement therapy (ERT) for Pompe disease represented a unique set of circumstances and individuals that helped to bring about this change and, in doing so, created a model that has had far wider applications., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Primary sclerosing cholangitis (PSC) is a chronic progressive disorder of unknown aetiology characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include itch and lethargy and in advanced cases cholangitis and end-stage liver disease, however increasing numbers of asymptomatic individuals are being identified. The disease is rare in the general population but is strongly associated with inflammatory bowel disease (IBD) affecting up to 5% of patients with ulcerative colitis, with a slightly lower prevalence (up to 3.6%) in Crohn's disease. The strength of this association means that the vast majority (> 90%) of patients with PSC also have IBD, although many may have only mild gastro-intestinal symptoms. Usually IBD presents before PSC, although vice-versa can occur and the onset of both conditions can be separated in some cases by many years. Mean age of diagnosis of PSC is in the fifth decade of life with a strong male predominance. Risk is increased in those with a family history of PSC, suggesting a genetic predisposition and the disease is almost exclusive to non-smokers. The ulcerative colitis associated with PSC is characteristically mild, runs a quiescent course, is associated with rectal sparing, more severe right sided disease, backwash ileitis and has a high risk of pouchitis post-colectomy. Most worrisome is the high risk of colorectal malignancy which necessitates routine colonoscopic surveillance. Cholangiocarcinoma is also a frequent complication of PSC with a 10%-15% lifetime risk of developing this condition. Treatment with high dose ursodeoxycholic acid offers some chemoprotective effects against colorectal malignancy and may decrease symptoms, biochemical and histological progression of liver disease. Small duct PSC patients characteristically have normal cholangiography, and liver biopsy is required for diagnosis, it appears to have a more favourable prognosis. Autoimmune Hepatitis (AIH) is also more prevalent in patients with IBD, with up to 16% of patients with AIH also having ulcerative colitis. A small subgroup of patients have a AIH-PSC overlap syndrome and the management of these patients depends on liver histology, serum IgM levels, autoantibodies, degree of biochemical cholestasis and cholangiography as some of these patients may respond to immunosuppression.

Plasma from patients with liver failure may contain toxic molecules that cause hepatocyte apoptosis and worsen liver disease, suggesting that removal of pro-apoptotic factors is an appropriate therapeutic strategy. We investigated the apoptosis of human hepatocytes induced by plasma from patients with both acute and acute-on-chronic liver disease, and the effect of molecular adsorbent dialysis (molecular adsorbent recirculation system [MARS] dialysis) on this. Apoptotic effects of acute and acute-on-chronic liver failure plasmas from 46 patients were assessed on cultured primary human hepatocytes using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) labeling and caspase 3 activation. In 11 patients undergoing MARS dialysis, the pro-apoptotic effect of their plasma was analyzed before and after therapy. Acute liver failure plasma induced more apoptosis than normal plasma (within 4-6 h of culture, a 2.5-fold increase by TUNEL labeling, 1.8-fold by caspase 3 activation), via a pathway involving caspase 8, suggesting involvement of the death-receptor pathway. However, not all acute liver failure plasmas were significantly more pro-apoptotic than normal plasma. Plasma from patients with acutely decompensated chronic liver disease induced apoptosis at the same rate as normal plasma. MARS dialysis improved biochemical parameters indicating effective removal of albumin-bound molecules, but the apoptotic effects of the plasma were unchanged. Thus, plasma of patients with acute liver failure, compared to normal plasma, induced increased apoptosis of primary human hepatocytes by a caspase-8- and caspase-3-dependent pathway. The apoptosis induced in the presence of liver failure plasma was not reduced by MARS dialysis.

Background and Goals: The 13C-methacetin breath test (MBT) measures the activity of the cytochrome P450 dependent enzyme system and has been developed to assess the functional hepatic mass. We evaluated simple modifications of the 13C-MBT to further increase its practicability and therefore clinical acceptance., Study: One hundred and four patients with different chronic liver diseases (including 35 patients with histologically proven cirrhosis) and 65 healthy controls underwent the 13C-MBT. Breath test results of 2-point measurements were compared with conventional breath test results (cumulative recovery after 30 min) and liver histology., Results: The 2-point-measurement at 0 and 15 minutes (with a cut-off <14.6 per thousand delta over baseline) had 92.6% sensitivity and 94.1% specificity in identifying the presence of cirrhosis compared with liver histology. The 2-point-measurements at 5 and 10 minutes also provided good discrimination between cirrhotic and noncirrhotic patients., Conclusions: The 13C-MBT using 2-point-measurement of breath samples at baseline and after 15 minutes reliably indicates decreased liver function in liver cirrhosis. This simplification of the 13C-MBT will increase practicability and cost efficiency, thus facilitating its clinical acceptability.

In toxic liver injury, proliferation of preexisting hepatocytes helps restore liver mass and function. While loss of liver mass per se stimulates hepatocyte proliferation, exogenous mitogens have a potential role in enhancing liver regeneration. The aim of this study was to characterize the effects of the mitogen, tri-iodothyonine, on the regenerative capacity of hepatocytes during thioacetamide-induced liver failure. Rats received (two) thioacetamide injections and, 12 hr later, either tri-iodothyonine or vehicle-only control. Liver cell proliferation was assessed and comparison made with other control groups receiving tri-iodothyonine or vehicle only. In rats with thioacetamide-induced hepatitis the proportion of hepatocytes in S-phase was greater in the tri-iodothyonine group (27+/-3.5%) compared to the vehicle-only group (20+/-2.5%; P < 0.05), with, notably, a greater number of midzonal (BrdU) positive hepatocytes in the tri-iodothyonine group. We conclude that the ability of hepatocytes in the midzonal areas of rat liver to proliferate in response to tri-iodothyonine is maintained during severe acute toxic injury.

Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive condition characterized by intermittent episodes of pruritus and jaundice that may last days to months. Treatment is often ineffective and symptoms, particularly pruritus, can be severe. Extracorporeal albumin dialysis (molecular adsorbent recycling system, MARS) is a novel treatment which removes albumin bound toxins including bilirubin and bile salts. We describe a case of a 34-year-old man with BRIC and secondary renal impairment who, having failed standard medical therapy, was treated with MARS. The treatment immediately improved his symptoms, renal and liver function tests and appeared to terminate the episode of cholestasis. We conclude that MARS is a safe and effective treatment for BRIC with associated renal impairment.