Examining dietary interventions in Crohn’s disease

This editorial builds on the article by Shakhshir et al.We conducted an overview of evidence-based dietary interventions in adults with inflammatory bowel disease(IBD).In the IBD population,there may be a role for the Mediterranean diet due to its anti-inflammatory effects,long-term sustainability,and role in improving cardiovascular health.In active Crohn’s disease,the use of exclusive enteral nutrition,the Crohn’s disease exclusion diet,or the specific carbohydrate diet may be used as a short-term adjunct to medical therapy and may improve mucosal healing.The low-FODMAP diet can assist in reducing symptoms for patients without evidence of active bowel inflammation.As interest in nutritional therapy increases amongst clinicians and patients alike,it is integral that dietary therapies are understood and discussed in routine management of patients with IBD as part of holistic care,ideally through a multidisciplinary setting with involvement of experienced dietitians.This serves to improve clinician-patient engagement and reduce complications of IBD including micro and micronutrient deficiencies.

Approach to loss of response to advanced therapies in inflammatory bowel disease

BACKGROUND Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease.Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients.However,issues of primary non-response(PNR)and secondary loss of response(SLOR)to non-tumour necrosis factor inhibitor(TNFi)therapies remains a common problem.Specific issues include the choice of optimization of therapy,identifying when dose optimization will recapture response,establishing optimal dose for escalation and when to switch therapy.AIM To explores the issues of PNR and SLOR to non-TNFi therapies.METHODS This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR.It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring(TDM).RESULTS In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin(IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response.For Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response.CONCLUSION The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.

Time to clinical response and remission for therapeutics in inflammatory bowel diseases: what should the clinician expect, what should patients be told?

An awareness of the expected time for therapies to induce symptomatic improvement and remission is necessary for determining the timing of follow-up, disease(re)assessment, and the duration to persist with therapies, yet this is seldom reported as an outcome in clinical trials. In this review, we explore the time to clinical response and remission of current therapies for inflammatory bowel disease(IBD) as well as medication, patient and disease related factors that may influence the time to clinical response. It appears that the time to therapeutic response varies depending on the indication for therapy(Crohn's disease or ulcerative colitis). Agents with the most rapid time to clinical response included corticosteroids, calcineurin inhibitors, exclusive enteral nutrition, aminosalicylates and anti-tumor necrosis factor therapy which will work in most patients within the first 2 mo. Vedolizumab,methotrexate and thiopurines had a longer time to clinical response and can take several months to achieve maximal efficacy. Factors affecting the time to clinical response of therapies included use of concomitant therapy, disease duration, smoking status, disease phenotype and advanced age. There appears to be marked variation in time to clinical response for therapies used in IBD which is further influenced by disease and patient related factors. Understanding the expected time to therapeutic response is integral to inform further decision making, maintain a patientcentered approach and ensure treatment is given an appropriate timeframe to achieve maximal benefit prior to cessation.

Natural history of chronic hepatitis B:Phases in a complex relationship

Chronic hepatitis B(CHB)is a condition of globalprevalence and its sequelae include cirrhosis and hepatocellular carcinoma.The natural history of CHB isa complex interplay of virological,environmental andhost factors.The dynamic relationship between thevirus and host evolves over the duration of the infection and different phases of the disease have been observed and described.These have been conceptualizedin terms of the state of balance between the host immune system and the hepatitis B virus and have beengiven the labels immune tolerant,immune clearance,immune control and immune escape although othernomenclature is also used.Host factors,such as age atinfection,determine progression to chronicity.Virological factors including hepatitis B viral load,mutationsand genotype also have an impact on the adverseoutcomes of the infection,as do hepatotoxic cofactorssuch as alcohol.Our understanding of the natural history of CHB has evolved significantly over the past fewdecades and characterizing the phase of disease ofCHB remains an integral part of managing this virus in the clinic.

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

Nasopharyngeal carcinoma （NPC） is a common cancer in Southern China and Southeast Asia. The disease is a poorly differentiated carcinoma without effective cure, and the mechanism underlying its development remains largely unknown. Of several factors identified in NPC aetiology in recent years, Epstein-Barr virus （EBV） infection has emerged to be most important. In almost all NPC cells, EBV uses several intracellular mechanisms to cause oncogenic evolution of the infected cells. One such mechanism by which EBV infection induces cellular immortalization is believed to be through the activation of telomerase, an enzyme that is normally repressed but becomes activated during cancer development. Studies show that greater than 85% of primary NPC display high telomerase activity by mechanisms involving EBV infection, consistent with the notion that EBV is commonly involved in inducing cell immortalization. More recently, different EBV proteins have been shown to activate or inhibit the human telomerase reverse transcriptase gene, by modulating intracellular signalling pathways. These findings suggest a new model with a number of challenges towards our understanding, molecular targeting and therapeutic intervention in NPC.

Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice

Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition of telomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase （TERT） gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter teiomeres in the adrenal cortex than that in wild-type （WT） control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.

Mesalazine preparations for the treatment of ulcerative colitis: Are all created equal?

Oral mesalazine(also known as mesalamine) is a 5-aminosalicylic acid compound used in the treatment of mild to moderate ulcerative colitis, with high rates of efficacy in induction and maintenance of remission.The therapeutic effect of mesalazine occurs topically at the site of diseased colonic mucosa. A myriad of oral mesalazine preparations have been formulated with various drug delivery methods to minimize systemic absorption and maximise drug availability at the inflamed colonic epithelium. It remains unclear whether different oral mesalazine formulations are bioequivalent. This review aims to evaluate the differences between mesalazine formulations based on the currently available literature and explore factors which may influence the selection of one agent above another.

Is there a difference in adenoma detection rates between gastroenterologists and surgeons?

AIM To compare the adenoma detection rate(ADR) between gastroenterologists and colorectal surgeons at Box Hill Hospital, Melbourne, Australia.METHODS A total of 300 colonoscopies performed by gastroenterologists and colorectal surgeons at Box Hill Hospital were retrospectively reviewed from May 2016 to June 2017. Exclusion criteria were: Patients ≤ 50 years old, colonoscopies with failure of caecal intubation, patients who previously had colon cancer and/or a colonic resection, history of polyposis syndromes or inflammatory bowel disease, or a colonoscopy within the last 10 years. Patient demographics, indications, symptoms and procedural-related outcomes were measured.RESULTS The ADR was not significantly different between gastroenterologists and colorectal surgeons(34% vs 34.67%; P = 0.90). The adjusted odds ratio correcting for gender, age, 1^(st) degree relative with colorectal cancer, previous colonoscopy, trainee involvement and caecal or terminal ileum intubation rate was 1.19(0.69-2.05).CONCLUSION Both specialties at our institution exceed benchmark standards suggested by published Australian and American guidelines. An association between endoscopist specialty and ADR was not observed.

Satisfaction with patient-doctor relationships in inflammatory bowel diseases:Examining patient-initiated change of specialist

AIM:To assess the reasons for,and factors associated with,patient-initiated changes in treating specialist in inflammatory bowel diseases(IBD).METHODS:Prospectively identified IBD patients(n = 256) with ≥ 1 encounter at a metropolitan hospital were surveyed,including whether they had changed treating specialist and why.Negative reasons included loss of confidence,disagreement,and/or personality clash with the specialist.RESULTS:Of 162 respondents,70(43%) had ever changed specialists;30/70(43%) for negative reasons,52/70(74%) in the preceding year.Patients with negative reasons for changing(n = 30) were younger(median,35.2 years vs 45.3 years),had higher IBD knowledge(median,5.0 years vs 4.0 years),yet had lower medication adherence and satisfaction scores(median,19.0 years vs 22.0 years,14.0 years vs 16.0 years respectively,Mann-Whitney tests,all P < 0.05),compared to all other responders(n = 132).Patients with a recent change(for any reason) were more likely to have Crohn's disease,currently active disease,previous bowel resection and recent hospitalization [OR 2.6,95% CI(1.3-5.4),2.2(1.0-4.7),5.56(1.92-16.67),2.0(1.3-3.0),eachP < 0.05].CONCLUSION:Changing specialist appears associated with patient-related(age,nonadherence) and contemporaneous disease-related factors(recent relapse) which,where modifiable,may enhance patient-doctor relationships and therefore quality of care.

Dysphagia: Thinking outside the box

Dysphagia is a common symptom that is important to recognise and appropriately manage, given that causes include life threatening oesophageal neoplasia, oropharyngeal dysfunction, the risk of aspiration, as well as chronic disabling gastroesophageal reflux(GORD). The predominant causes of dysphagia varies between cohorts depending on the interplay between genetic predisposition and environmental risk factors, and is changing with time. Currently in white Caucasian societies adopting a western lifestyle, obesity is common and thus associated gastroesophageal reflux disease is increasingly diagnosed. Similarly, food allergies are increasing in the west, and eosinophilic oesophagitis is increasingly found as a cause. Other regions where cigarette smoking is still prevalent, or where access to medical care and antisecretory agents such as proton pump inhibitors are less available, benign oesophageal peptic strictures, Barrett's oesophagus, adeno-as well as squamous cell carcinoma are endemic. The evaluation should consider the severity of symptoms, as well as the pretest probability of a given condition. In young white Caucasian males who are atopic or describe heartburn, eosinophilic esophagitis and gastroesophageal reflux disease will predominate and a proton pump inhibitor could be commenced prior to further investigation. Upper gastrointestinal endoscopy remains a valid first line investigation for patients with suspected oesophageal dysphagia. Barium swallow is particularly useful for oropharyngeal dysphagia, and oesophageal manometry mandatory to diagnose motility disorders.

Transitioning patients with inflammatory bowel disease from hospital-based to rapid home-based infliximab: A stepwise, safety and patient-orientated process towards sustainability

BACKGROUND Infliximab and other intravenous biologic infusions are increasingly used for chronic disorders like inflammatory bowel disease(IBD).Rapid infliximab and home-based infusions are attractive solutions to address resource and capacity issues for infusion centres,yet infliximab infusion reactions reportedly occur in up to 25%of patients with IBD,even at the manufacturers’recommended infusion duration of 2 h.AIM To evaluate the safety,cost and patient satisfaction of transitioning from hospitalbased,standard 2 h to rapid home-based,30-min infliximab infusions.METHODS All patients receiving rapid infliximab infusions for IBD between 2014 to 2017(39 mo)were compared with those who received standard two-hour IFX infusions between 2005-2013(96 mo)at a single IBD centre.Data(per-infusion and perindividual)including adverse drug reactions(ADR),duration(based on needledeparture time)and other clinical data were extracted from electronic medical records.Multivariable logistical regression analysis assessed factors potentially associated with increased risk of ADRs to rapid infusions.The primary outcome was the safety[as per relative risk(RR)of (ADR)of(1)rapid 30 m infusions(both hospital-and home-based)vs standard 2 h infliximab infusions.Also,relative cost per infusion and patient satisfaction and productivity were evaluated in rapid infusion recipients who transitioned to home-based infusions.RESULTS Of 129 patients who received 1461 rapid IFX infusions(2014-2017)were compared with 169 patients who received 2214 standard IFX infusions(2005-2013).Within the rapid cohort,55(42.6%)were males,median age 42 years(range 18,86),114(84%)had Crohn’s disease(CD)with a median disease duration 5 years(0,36).Median needle to departure time was higher in the standard than the rapid protocol group,108(70,253)vs 50(33,90)min,(P<0.001),with a per infusion cost of$AUD 107.50 vs$49.77,respectively(both P<0.001).There was no difference in median infusion duration or costs between rapid home vs hospital-based infusions(P=0.21).8 patients in the rapid infliximab cohort had an ADR compared with 23 standard infliximab recipients(RR 0.55%vs 1.04%respectively),hence a higher likelihood of ADR with standard compared to rapid infusions[RR 3.0,95%CI(1.2,7.7),P=0.02].No ADRs were observed in 405 rapid home-based infusions.A lower body mass index(<22 kg/m2),presence of one or more extra intestinal manifestations,longer disease duration(>3 years)and previous exposure to another biologic were each independently associated with a higher likelihood of reaction(s)to rapid infusions.All(100%)survey respondents preferred the rapid vs standard infusions,however within rapid infusion recipients,61.3%found home based infusions more inconvenient than hospitalbased infusions despite a median of 0 h per week missed from paid work and no self-reported loss of work productivity.CONCLUSION Transitioning to rapid infliximab infusions appears very safe with significant cost benefit,patient satisfaction and avails the provision of safe,efficient,home-based infliximab infusions by IBD centres worldwide.

A case of giant prostatic hyperplasia

Benign prostatic hyperplasia(BPH)is one of the most common conditions experienced by aging males and a frequent cause of bladder outlet obstruction and macroscopic haematuria.Giant prostatic hyperplasia(GPH)is an extremely rare form of prostatic hyperplasia.We present a case of a patient with GPH of 800 mL.To our knowledge,this is the fourth largest prostatic hyperplasia ever reported in the literature.

Outcomes of a drug shortage requiring switching in patients with ulcerative colitis

BACKGROUND Drug shortages are common yet their impact on patient care and their commercial ramifications has not been adequately researched.In Australia a shortage of balsalazide(2012-2013)necessitated substitution with alternative 5-aminosalicylate(5-ASA)formulations for ulcerative colitis(UC).AIM To assess and compare the clinical and commercial sequelae of non-medical switching from balsalazide to another 5-ASA and/or return to balsalazide once supply resumed.METHODS A prospective cohort study of patients on balsalazide for mild-moderate UC was conducted where,strictly due to the national shortage(November 2012-January 2013),were switched to alternative 5-ASA and/or then returned to balsalazide once supply resumed.Clinical(Partial Mayo),endoscopic(Mayo score)activity,adverse effects(to alternative 5-ASA)and percentage market share(of continuous 5-ASA users)from baseline(i.e.,time of switching due to shortage)through to five years were assessed.RESULTS Of 31 patients switched due to the shortage,12(38.7%)resumed balsalazide immediately once supply resumed,8(25.8%)prompted by adverse effects to the alternative 5-ASA used.Three patients(9.7%)had documented symptomatic improvement,15(48.4%)were unchanged and 13(41.9%)had symptomatic worsening vs baseline(P<0.01),after switching to an alternative 5-ASA.At 3 and 5y post switch,overall 26/31(83.9%)and 23/31(74.2%)had remained continuously on any 5-ASA therapy respectively.Twelve(38.7%)and 11(35.5%)patients remained on balsalazide continuously at three and five years respectively after drug supply returned,equating to a loss of market share(within 5-ASA class)of 45.2%and 38.7%respectively.CONCLUSION This study of a balsalazide shortage in UC patients exemplifies the detrimental impact of a drug shortage on long term patient,disease and commercial outcomes.

Estrogen deficiency reversibly induces telomere shortening in mouse granulosa cells and ovarian aging in vivo

Estrogen is implicated as playing an important role in aging and tumorigenesis of estrogen responsive tissues;however the mechanisms underlying the mitogenic actions of estrogen are not fully understood.Here we report that estrogen deficiency in mice caused by targeted disruption of the aromatase gene results in a signi-ficant inhibition of telomerase maintenance of telomeres in mouse ovaries in a tissue-specific manner.The inhibition entails a significant shortening of telomeres and compromised proliferation in the follicular granulosa cell compartment of ovary.Gene expression analysis showed decreased levels of proto-oncogene c-Myc and the telomerase catalytic subunit,telomerase reverse transcriptase(TERT),in response to estrogen deficiency.Estrogen replacement therapy led to increases in TERT gene expression,telomerase activity,telomere length and ovarian tissue growth,thereby reinstating ovary development to normal in four weeks.Our data demonstrate for the first time that telomere maintenance is the primary mechanism mediating the mitogenic effect of estrogen on ovarian granulosa cell proliferation by upregulating the genes of c-Myc and TERT in vivo.Estrogen deficiency or over-activity may cause ovarian tissue aging or tumorigenesis,respectively,through estrogen regulation of telomere remodeling.

TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence

Human telomerase reverse transcriptase （hTERT） plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 （BMP7） induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.

Molecular dynamics and principal components of potassium binding with human telomeric intra-molecular G-quadruplex

Telomere assumes intra-molecular G-quadruplex that is a significant drug target for inhibiting telomerase main- tenance of telomeres in cancer. Metal cations have been recognized as playing important roles in stabilizing G-quadruplex, but their binding processes to human telomeric G-quadruplex remain uncharacterized. To in- vestigate the detailed binding procedures, molecular dynamics simulations were conducted on the hybrid [3 ＋ 1] form-one human telomeric intra-molecular G-quadruplex. We show here that the binding of a potas- sium ion to a G-tetrad core is mediated by two alternative pathways. Principal component analysis illustrated the dominant concerted motions of G-quadruplex occurred at the loop domains. MM-PBSA calculations revealed that binding was energetically favorable and driven by the electrostatic interactions. The lower binding site was found more constructive favorable for binding. Our data provide useful information on a potassium-mediated stable structure of human telomeric intra-molecular G-quadruplex, implicating in ion disorder associated conformationa｜ changes and targeted drug design.

New-onset of celiac disease during interferon-based therapy for hepatitis C

We present the case of a patient who first developed symptoms of celiac disease while on interferon-based therapy for treatment of chronic hepatitis C.He required hospital admission for symptom management and diagnostic work-up of severe diarrhoea.He made a rapid recovery with a gluten-free diet and was able to continue therapy.Consideration should be given to screening for celiac disease prior to the commencement of interferon-based therapy,particularly in highprevalence populations.