Search

Background: Long specialist outpatient waiting lists are a source of clinical risk. Triage assignment is based on subjective assessment of referrals and fails to account for dynamic changes in disease status while patients await clinical review. Aims: To pilot an innovative triage method using a trifold approach to conduct noninvasive assessment of fibrosis and to determine the feasibility of reflex hepatitis C virus (HCV) polymerase chain reaction (PCR) testing. Methods: A total of 1006 patients awaiting an initial liver clinic appointment at a tertiary Australian hospital were sent a short message service (SMS) requesting a blood test be completed. The first 60 patients received an SMS only, and the subsequent 946 patients also received a phone call from a Liver Care Guide (LCG), a nonclinician employed to increase patient engagement. Liver fibrosis assessment through noninvasive testing was performed using an aspartate aminotransferase to platelet ratio index (APRI) and fibrosis‐4 (FIB4) score. Patients with an APRI ≥1, FIB4 ≥3.25 or positive HCV PCR were retriaged to Category 1. Results: Four hundred ninety (49%) patients completed testing and 40 (4%) were triaged to Category 1. Subanalyses demonstrated increased response rates with LCG input (P = 0.012). Retriaged patients had been on the waitlist for a median of 216 days, exceeding initial category recommendations. Conclusion: This study successfully implemented a semiautomated strategy that prioritises patients with probable advanced liver disease or active HCV, demonstrating enhanced patient engagement with LCG support. It highlights the burden of patients referred for specialist care and the need for innovative strategies for monitoring and objective risk stratification. [ABSTRACT FROM AUTHOR]

Simple Summary: Crofton weed toxicity, caused by Ageratina adenophora, has been recognized as a cause of fatal lung disease in horses for over a century. Despite its impact on horse health in many areas of the world, the toxic syndrome is poorly understood and understudied. This paper looks at the prior research on weed biology, the potential toxicology mechanisms, and the pathology in horses and other species, as well as the future directions to improve our understanding of this fatal toxic weed affecting horses. Crofton weed (Ageratina adenophora) is a global and highly invasive weed, with ingestion causing severe respiratory disease in horses, leading to irreversible and untreatable pulmonary fibrosis and oedema. While reports of equine pneumotoxicity remain common in Australia and New Zealand, equine pneumotoxicity may be underdiagnosed in other countries where Crofton weed is endemic but poorly differentiated. The pathogenesis of Crofton weed toxicity following ingestion has been well described in a number of different animal models, including rodents, rabbits, and goats. However, induced toxicity is organ-selective across different animal species, and these vastly differ from the pathogenesis described in horses, both clinically and after experimental exposure. Sources of variation may include species-specific susceptibility to different toxins present in the plant, different mechanistic processes of toxicity, and species differences in toxin biotransformation and bioactivation across different organs. Considering disease severity and Crofton weed's invasiveness globally, assessing published toxicological and exposure data is necessary to advance research, identify specific toxins for horses, and possible prophylactic and therapeutic strategies. This review presents an overview of the available literature on equine toxicity, parallels between toxicity in horses and other animal species, and important aspects to be included in the future research agenda. [ABSTRACT FROM AUTHOR]

Metabolic Associated Fatty Liver Disease (MAFLD) is the most common cause of liver disease in Australia, but prevalence data are limited. We aimed to describe the frequency of alanine aminotransferase (ALT) elevation, and MAFLD within a large prospective Australian cohort. Cross-sectional analysis of the 2012 survey of the Australian Diabetes, Obesity and Lifestyle (AusDiab) study which included 4747 Australian adults (aged 34–97 yrs) was performed. Frequency of ALT elevation (men ≥ 40 IU/L, women ≥ 30 IU/L) and MAFLD (Fatty Liver Index (FLI) > 60 alongside metabolic risk factors) was determined and risk of advanced fibrosis stratified using the BARD score. Elevated ALT was found in 13% of the cohort, including 22% of people with diabetes, 18% with obesity, and 17% with the metabolic syndrome. 37% of the cohort had MAFLD, and those with MAFLD were more likely to be older (OR 1.01 per 1 year (95% CI 1.00–1.02)), male (OR 1.37 (95% CI 1.17–1.59)), have ALT elevation (OR 3.21 (95% CI 2.59–3.99)), diabetes (OR 3.39 (95% CI 2.61–4.39)), lower HDL-C (OR 0.15 per 1 mmol/L (95% CI 0.12–0.19)), higher diastolic blood pressure (OR 1.05 per 10 mmHg (95% CI 1.05–1.06)), a sedentary lifestyle (OR 1.99 (95% CI 1.59–2.50)) and less likely to have tertiary education (OR 0.81 (95% CI 0.7–0.94) compared to those without MAFLD. Of those with MAFLD, 61% had a BARD score suggesting risk of advanced fibrosis and 22% had an elevated ALT. Over 10% of this Australian cohort had elevated ALT, and 37% had MAFLD, with many at risk for advanced fibrosis. [ABSTRACT FROM AUTHOR]

Background: Current guidelines suggest using transient elastography (TE) or aspartate aminotransferase to platelet ratio index (APRI) score <1 to exclude cirrhosis prior to commencing treatment for hepatitis C virus (HCV). Recently, fibrosis‐4 (FIB‐4) <0.93 has been shown to have a high negative predictive value (NPV) for the presence of cirrhosis. Aims: To assess FIB‐4 and APRI in a cohort of HCV patients and to validate FIB‐4 <0.93 in populations of HCV‐infected individuals with differing cirrhosis prevalence, including secondary care, primary care and prisons. Methods: From our treatment database, we identified patients with complete data (n = 793). We calculated FIB‐4 and APRI and correlated this with the presence of cirrhosis, determined by TE. We analysed the performance of FIB‐4 and APRI using area under the receiver operating curve analysis. We calculated sensitivity, specificity, positive predictive value, NPV and number of patients misclassified using published cut‐offs in populations with varying cirrhosis prevalence. Results: FIB‐4 was superior to APRI for the diagnosis of cirrhosis (area under the receiver operating curve 0.868 vs 0.802). In secondary care (cirrhosis prevalence 32%), APRI <1 had a NPV of 80% and misclassified 14% of patients. FIB‐4 <0.93 had a NPV of 97% and misclassified 1%. In primary care and prison (cirrhosis prevalence 13% and 8%), the NPV for APRI <1 was 93% and 96%, respectively, but 5% of patients with cirrhosis were misclassified. FIB‐4 <0.93 had excellent NPV in both primary care (97%) and prisoners (100%). Conclusions: FIB‐4 <0.93 is highly efficient at ruling out cirrhosis in HCV patients and allows TE to be appropriately avoided, thereby streamlining treatment algorithms. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in Australia and its recent increase mirrors the obesity and type 2 diabetes epidemics. Currently, many patients who present to primary care with abnormal liver function tests or steatosis on liver ultrasound are referred for assessment in secondary care. Due to the large number of patients with NAFLD, this results in long waits for clinical and fibrosis assessment, placing unnecessary burden on the public hospital system.Methods: We will conduct a 1:1 parallel randomised trial to compare two alternative models of care for NAFLD. Participants will be randomised to usual care or the LOCal Assessment and Triage Evaluation (LOCATE) model of care and followed for 1 year. We will recruit patients from the non-neighbouring Sunshine Coast and Metro South Hospital and Health Services (HHSs) in Queensland, Australia. Our primary outcome of interest is time to diagnosis of high-risk NAFLD, based on the number of participants in each arm of the study who receive a diagnosis of clinically significant fibrosis. Two hundred and 34 participants will give us a 95% power to detect a 50% reduction in the primary outcome of time to diagnosis of high-risk disease. We will also conduct an economic evaluation, evaluating the cost-effectiveness of the new model of care. We will also evaluate the implementation of the new model of care.Discussion: It is anticipated that the results of this study will provide valuable new information regarding the management of NAFLD in the Australian setting. A relatively simple change to care could result in earlier identification of patients with significant liver disease and lower overall costs for the health system. Results will be directly disseminated to key staff for further distribution to consumers, policy- and decision-makers in the form of evidence briefs, plain language summaries and policy recommendations.Trial Registration: The trial was registered on 30 January, 2020 and can be found via ANZCTR - number ACTRN12620000158965. [ABSTRACT FROM AUTHOR]

Background and Aims: The burden of liver disease among people with diabetes at a population level is unknown. We explored the burden and trends of liver disease mortality and hospitalisations among Australians with diabetes., Methods: We linked Australians with type 2 diabetes on the National Diabetes Services Scheme to the National Death Index for 2002-2019 to determine trends in the proportion of deaths due to liver disease, overall and by subcategory. We also determined the leading reasons and risk factors for liver disease hospitalisations in those with diabetes over this period. Finally, we compared the burden of liver disease hospitalisations among those with diabetes to the general population using excess hospitalisations per 100 000 person-years., Results: Among Australians with type 2 diabetes (n = 1 122 431) liver diseases accounted for between 1.5% and 1.9% of deaths between 2002 and 2019, roughly one-third of the proportion of deaths caused by kidney disease. The proportion of deaths due to inflammatory liver diseases among those with diabetes increased from .08% in 2002 to .27% in 2019. Alcohol-related liver disease accounted for the greatest share (22.7%) of liver disease hospitalisation in those with diabetes, but the number of hospitalisations for this condition declined over time. Compared to the general population, men (RR 3.63, 95% CI 3.44-3.84) and women (RR 4.49, 4.21-4.78) with diabetes were at higher risk of hospitalisation for fibrosis and cirrhosis; however, this did not translate to a substantial excess risk per 100 000 population., Conclusions: Better screening methods for liver disease among people with diabetes should be developed and implemented into practice., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Idiopathic pulmonary fibrosis (IPF) is a progressive disease leading to significant morbidity and mortality. In 2017 the Thoracic Society of Australia and New Zealand (TSANZ) and Lung Foundation Australia (LFA) published a position statement on the treatment of IPF. Since that time, subsidized anti-fibrotic therapy in the form of pirfenidone and nintedanib is now available in both Australia and New Zealand. More recently, evidence has been published in support of nintedanib for non-IPF progressive pulmonary fibrosis (PPF). Additionally, there have been numerous publications relating to the non-pharmacologic management of IPF and PPF. This 2023 update to the position statement for treatment of IPF summarizes developments since 2017 and reaffirms the importance of a multi-faceted approach to the management of IPF and progressive pulmonary fibrosis., (© 2024 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Abstract: Background: Non‐alcoholic fatty liver disease (NAFLD) is a common cause of incidental liver test abnormalities. General practitioners (GP) have a key role in identifying people with NAFLD at risk of significant liver disease. Recent specialist guidelines emphasise the use of fibrosis algorithms or serum biomarkers rather than routine liver tests, to assess advanced fibrosis. Aim: To evaluate primary care clinicians’ current approach to diagnosis, management and referral of NAFLD. Methods: A cross‐sectional survey of primary care clinicians was undertaken through a structured questionnaire about NAFLD. A convenience sample of general practice clinics and general practice conferences in Metropolitan Brisbane and regional south east Queensland was selected. Results: A total of 108 primary care clinicians completed the survey (participation rate 100%). Fifty‐one percent of respondents considered the prevalence of NAFLD in the general population to be ≤10%. Twenty‐four percent of respondents felt that liver enzymes were sufficiently sensitive to detect underlying NAFLD. Most respondents were unsure whether the Fibrosis 4 score (62.7% unsure) or Enhanced Liver Fibrosis score (63.7% unsure) could help to identify advanced fibrosis or cirrhosis. Although 47% of respondents said they would refer a patient to a Gastroenterologist/Hepatologist if they suspect the patient has NAFLD, 44.1% do not make any referrals. Of concern, 70.6% of clinicians said they were unlikely to refer a patient to Hepatology unless liver function tests are abnormal. Conclusion: Our findings demonstrate that many primary care clinicians underestimate the prevalence of NAFLD and under‐recognise the clinical spectrum of NAFLD and how this is assessed. [ABSTRACT FROM AUTHOR]

As biota are increasingly exposed to plastic pollution, there is a need to closely examine the sub-lethal 'hidden' impacts of plastic ingestion. This emerging field of study has been limited to model species in controlled laboratory settings, with little data available for wild, free-living organisms. Highly impacted by plastic ingestion, Flesh-footed Shearwaters (Ardenna carneipes) are thus an apt species to examine these impacts in an environmentally relevant manner. A Masson's Trichrome stain was used to document any evidence of plastic-induced fibrosis, using collagen as a marker for scar tissue formation in the proventriculus (stomach) of 30 Flesh-footed Shearwater fledglings from Lord Howe Island, Australia. Plastic presence was highly associated with widespread scar tissue formation and extensive changes to, and even loss of, tissue structure within the mucosa and submucosa. Additionally, despite naturally occurring indigestible items, such as pumice, also being found in the gastrointestinal tract, this did not cause similar scarring. This highlights the unique pathological properties of plastics and raises concerns for other species impacted by plastic ingestion. Further, the extent and severity of fibrosis documented in this study gives support for a novel, plastic-induced fibrotic disease, which we define as ' Plasticosis,'. [Display omitted] • Extensive scar tissue formation was associated with plastic exposure in seabirds. • Plastic significantly altered collagen prevalence within stomach tissue structures. • Pathology was caused directly by plastic, rather than natural items, such as pumice. • First record of plastic-related fibrosis in seabird stomach tissues. • Evidence for a new plastic-induced fibrotic disease, ' Plasticosis'. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is the fastest increasing cause of cancer death in Australia. A recent Australian consensus guidelines recommended HCC surveillance for cirrhotic patients and non-cirrhotic chronic hepatitis B (CHB) patients at gender and age specific cut-offs. A cost-effectiveness model was then developed to assess surveillance strategies in Australia., Methods: A microsimulation model was used to evaluate three strategies: biannual ultrasound, biannual ultrasound with alpha-fetoprotein (AFP) and no formal surveillance for patients having one of the conditions: non-cirrhotic CHB, compensated cirrhosis or decompensated cirrhosis. One-way and probabilistic sensitivity analyses as well as scenario and threshold analyses were conducted to account for uncertainties: including exclusive surveillance of CHB, compensated cirrhosis or decompensated cirrhosis populations; impact of obesity on ultrasound sensitivity; real-world adherence rate; and different cohort's ranges of ages., Results: Sixty HCC surveillance scenarios were considered for the baseline population. The ultrasound + AFP strategy was the most cost-effective with incremental cost-effectiveness ratios (ICER) compared to no surveillance falling below the willingness-to-pay threshold of A$50,000 per quality-adjusted life year (QALY) at all age ranges. Ultrasound alone was also cost-effective, but the strategy was dominated by ultrasound + AFP. Surveillance was cost-effective in the compensated and decompensated cirrhosis populations alone (ICERs < $30,000), but not cost-effective in the CHB population (ICERs > $100,000). Obesity could decrease the diagnostic performance of ultrasound, which in turn, reduce the cost-effectiveness of ultrasound ± AFP, but the strategies remained cost-effective., Conclusions: HCC surveillance based on Australian recommendations using biannual ultrasound ± AFP was cost-effective., (© 2023. The Author(s).)

Coal workers' pneumoconiosis (CWP) is an untreatable but preventable lung disease arising from chronic inhalation of coal dust. Recent reports of CWP in Queensland, along with international data, suggest that there is a resurgence in pneumoconiosis. The prevalence of CWP varies considerably between countries. In Australia, there is no mandatory reporting system and no national data on the prevalence of CWP. The symptoms and manifestations of CWP vary depending on the composition of the inhaled dust, duration of exposure, stage of disease and host-related factors. CWP may develop into progressive massive fibrosis (PMF), which can be fatal. Radiological assessment should be performed according to evidence-based standards using the ILO (International Labour Office) International Classification of Radiographs of Pneumoconioses. As preventing exposure to coal dust prevents CWP, it is important to implement and enforce appropriate standards limiting exposure. In Australia, these standards currently vary between states and are not in keeping with international understanding of the levels of coal dust that cause disease. Longitudinal screening programs are crucial for monitoring the health of coal workers to identify individuals with early-stage disease and prevent progression from mild disease to PMF. We recommend: standardisation of coal dust exposure limits, with harmonisation to international regulations; implementation of a national screening program for at-risk workers, with use of standardised questionnaires, imaging and lung function testing; development of appropriate training materials to assist general practitioners in identifying pneumoconiosis; and a system of mandatory reporting of CWP to a centralised occupational lung disease register. [ABSTRACT FROM AUTHOR]

Background Evaluation of an outreach programme using a mobile transient elastography ( TE) device ( FibroScan) to improve liver disease assessment in different clinical settings. Aims To evaluate a programme of liver fibrosis assessment by TE and to compare fibrosis scores between different sites and patient groups. Methods Prospective cohort study. TE was conducted at a tertiary hospital and during outreach clinics in three different settings: community clinics, clinics for people who use drugs ( PWUD) and regional clinics in rural Victoria. All patients referred for TE at the participating locations were eligible during the study period. Results A total of 200 of 623 patients was assessed and evaluated during outreach sessions (regional 100; PWUD 18; community 82). While the majority of patients in community centres were infected with hepatitis B (68%), most patients in regional clinics and in PWUD settings had hepatitis C virus ( HCV) (81 and 100%, respectively). Significantly more patients assessed at regional clinics and PWUD settings presented with severe fibrosis ( F3-F4, F4): regional clinics 39%; PWUD 31%; tertiary 11%; community 7%, ( P <0.001). Multivariable logistic regression analysis revealed that older age, alcohol consumption, male sex, increased alanine transferase levels, HCV infection and importantly, evaluation at regional sites were independently associated with severe fibrosis. Conclusions A TE-based outreach programme allows for assessment of liver fibrosis in varied and regional populations. The finding that patients in regional settings and PWUD presented with more advanced fibrosis should prompt improvements in healthcare to improve access for these populations. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess factors associated with baseline knowledge of HCV and liver disease, acceptability of transient elastography (TE) assessment (FibroScan(®)), and willingness and intent to receive HCV treatment among persons with a history of injection drug use participating in a liver health promotion campaign.Methods: The LiveRLife campaign involved three phases: (1) campaign resource development; (2) campaign resource testing; and (3) campaign implementation. Participants were enrolled in an observational cohort study with recruitment at four clinics - one primary health care facility, two OST clinics, and one medically supervised injecting centre - in Australia between May and October 2014. Participants received educational material, nurse clinical assessment, TE assessment, dried blood spot testing, and completed a knowledge survey.Results: Of 253 participants (mean age 43 years), 68% were male, 71% had injected in the past month, and 75% self-reported as HCV positive. Median knowledge score was 16/23. In adjusted analysis, less than daily injection (AOR 5.01; 95% CI, 2.64-9.51) and no daily injection in the past month (AOR 3.54; 95% CI, 1.80-6.94) were associated with high knowledge (≥16). TE was the most preferred method both pre- (66%) and post-TE (89%) compared to liver biopsy and blood sample. Eighty-eight percent were 'definitely willing' or 'somewhat willing' to receive HCV treatment, and 56% intended to start treatment in the next 12 months. Approximately 68% had no/mild fibrosis (F0/F1, ≥2.5 to ≤7.4kPa), 13% moderate fibrosis (F2, ≥7.5 to ≤9.4kPa), 10% severe fibrosis (F3, ≥9.5 to ≤12.4kPa), and 9% had cirrhosis (F4, ≥12.5kPa).Conclusion: Liver disease and HCV knowledge was moderate. High acceptability of TE by PWID provides strong evidence for the inclusion of TE in HCV-related care, and could help to prioritise HCV treatment for those at greatest risk of liver disease progression. [ABSTRACT FROM AUTHOR]

Since the introduction of Transient Elastography ( TE) into Australia in 2008, non-invasive liver fibrosis assessments have integrated themselves into clinical hepatology. The Australian Liver Association ( ALA) recognizes these technologies perform an important role in the assessment of chronic viral hepatitis B and C. However, in the setting of viral hepatitis and many other chronic liver diseases, there remains no consensus or guidelines regarding the performance, utility or reporting of TE. Accordingly, the ALA sought to produce an expert consensus statement for the use of TE in chronic viral hepatitis. The recommendations incorporated in this document are based upon a thorough literature review and draw on extensive clinical experience using TE. The initial draft was presented at Australian Gastroenterology Week ( AGW) 2013. Through a collaborative process and expert external review a finalized document was presented at AGW 2014. [ABSTRACT FROM AUTHOR]

Significant advances have recently been made in the management of hepatitis C virus ( HCV) with many of the changes now part of routine clinical practice. These include the use of non-invasive methods to assess liver fibrosis, interleukin 28B genotype testing to predict interferon responsiveness and the use of new anti-viral regimens for HCV genotype 1. Two new antiviral agents (boceprevir and telaprevir) have recently become available in Australia. These protease inhibitors are used in combination with pegylated interferon and ribavirin as triple therapy for genotype 1 HCV. This combination increases sustained virological response from approximately 45-50% to 66-75% in treatment naïve patients. However, these new regimens present novel challenges including complicated treatment algorithms based on virological response, numerous drug interactions and additional side effects especially in patients with advanced fibrosis. The protease inhibitors are the first of many antiviral drugs to become available to treat HCV, heralding the arrival of new agents that will offer greater chances of cure with improved safety and tolerability compared with current therapies. [ABSTRACT FROM AUTHOR]

Background Insulin resistance ( IR) is a key factor in the development of hepatic steatosis and fibrosis in chronic hepatitis C virus infection. Little is known about the impact of viral clearance on IR. Aim The aim of this study was to determine the impact of viral clearance on IR. Methods Eighty-six patients treated according to standard clinical practice at an Australian teaching hospital between 2003 and 2007 were prospectively studied. Demographic, biochemical and histological data were collected. Results The mean pretreatment homeostatic model assessment- IR ( HOMA-IR) was similar in the sustained virological response ( SVR) and non- SVR groups (2.7 ± 0.5 and 2.8 ± 0.4, respectively), and both values were consistent with significant IR. There was a significant improvement in HOMA-IR (from 3.0 ± 1.0 to 2.2 ± 0.5, P = 0.04) at the end of treatment in the SVR group only. This trended towards significance at 6 months post-treatment. Multiple regression analysis found improvement in both gamma-glutamyl transpeptidase and alanine aminotransferase predicted improvement in HOMA-IR when controlled for other potential factors ( P = 0.01). Conclusions Hepatitis C virus clearance is associated with improvement in IR. Although baseline hepatic fibrosis is a predictor of IR, changes in IR appear to be independent of changes in liver fibrosis. Treatment-related improvement in gamma-glutamyl transpeptidase and alanine aminotransferase seen with improved IR may be a possible marker of reduction of hepatic oxidative stress. [ABSTRACT FROM AUTHOR]

Background and Aim To assess the cost-effectiveness of hepatitis C virus treatment with pegylated interferon alfa-2a and ribavirin in current and former people who inject drugs ( PWID). Methods A decision analytic model simulated the lifetime costs and outcomes of four treatment options: early treatment with mild fibrosis, standard treatment with moderate fibrosis, late treatment with compensated cirrhosis, and no treatment. Treatment modalities were simulated across current, former, and never-injector cohorts of 1000 hypothetical patients with chronic hepatitis C virus. The main outcome measures were incremental costs ($ AUD) per quality-adjusted life years ( QALYs) gained, and incremental cost-effectiveness ratios ( ICERs) were calculated for each cohort. Results Treatment of current PWID during mild fibrosis resulted in a discounted average gain of 1.60 QALYs (95% confidence interval 0.93-2.26) for an added cost of $12 723 ($11 153-$14 396) compared with no treatment, yielding an ICER of $7941 per QALY gained ($6347-$12 017). Former PWID gained 1.80 QALYs (1.29-2.33) for $10 441 ($8843-$12 074) for early treatment compared with no treatment, resulting in an ICER of $5808 per QALY gained ($5189-$6849). Never-injectors gained 2.33 QALYs (1.87-2.80) for $9290 ($7642-$10 912) compared with no treatment-an ICER of $3985 per QALY gained ($3896-$4080). Early treatment was more cost-effective than late treatment in all cohorts. Conclusions Despite comorbidities, increased mortality, and reduced adherence, treatment of both current and former PWID is cost-effective. Our estimates fall below the unofficial Australian cost-effectiveness threshold of $ AUD 50 000 per QALY for public subsidies. Scaling up treatment for PWID can be justified on purely economic grounds. [ABSTRACT FROM AUTHOR]

Background: Appropriate management of lymphoedema requires an accurate diagnosis of the changes in fibrotic induration in order to target treatment. Tonometry is used to measure tissue's resistance to compression and provide an objective assessment of the stage of lymphoedema, tissue changes and treatment efficacy. The mechanical tonometer that is commonly used has some shortcomings, as the display is difficult to read and has to be read while in place on the limb. A new tool, the indurometer, has been designed to replicate the function of the tonometer, but overcome its shortcomings. Aims: This study compared a prototype indurometer with the original mechanical tonometer. Methods: A prototype indurometer and an original tonometer were used to measure fibrotic induration levels on 22 subjects with secondary arm lymphoedema taken at six points on each patient's body. The results were analysed for repeatability using a coefficient of variation and the usability of each device was considered. Results: The results from the indurometer had a similar repeatability to the tonometer. The tonometer had consistent repeatability at all measurement sites and, while similarly good, the indurometer's repeatability deteriorated for measurements at the anterior chest. Conclusion: Some changes will need to be made to the indurometer's design to make measurements more repeatable. Declaration of interest: Olivia Pallotta and Mark McEwen are employed by Flinders Biomedical Enterprises Pty Ltd. [ABSTRACT FROM AUTHOR]

Background: Liver biopsy remains the gold standard for characterizing and evaluating treatment response in nonalcoholic fatty liver disease (NAFLD). Liver heterogeneity and sampling variability can affect the reliability of results. This study aimed to compare histological variability of intraoperative wedge and core liver biopsies from different lobes in bariatric patients, to better inform surgeons on biopsy method and guide interpretation of results., Methods: We prospectively recruited bariatric surgical patients. Intraoperative core biopsies were taken from the left and right lobe, with a wedge biopsy taken from the left. All biopsies were graded by a specialist liver pathologist, blinded to clinical details and biopsy site. Concordance of histological findings between sites was evaluated., Results: There were 91 participants (72.2% female), mean age 46.8 ± 12.0 years, body mass index 45.9 ± 9.4 kg/m 2 . There was no significant pattern for up- or down-grading disease dependent on biopsy technique. Moderate to strong agreement was seen in the presence of NAFLD and nonalcoholic steatohepatitis (NASH, κ = 0.609-0.865, p < 0.001) between biopsy sites. Individual components (steatosis, inflammation, ballooning) showed weaker agreement (κ = 0.386-0.656, p < 0.01). Fibrosis showed particularly poor agreement (κ = 0.223-0.496, p < 0.01). Detection of pathology improved with a combination of biopsy techniques, compared to a single biopsy method., Conclusion: Overall diagnosis of NAFLD or NASH shows good agreement between biopsy sites, but individual components, particularly fibrosis stage, vary significantly. Clinicians should consider biopsies from varied sites, to better assess liver disease severity. These data have important implications in fibrosis assessment of NAFLD and are relevant in the interpretation of histological efficacy of investigational pharmacotherapies., Trial Registration: ACTRN12615000875505 (Australian Clinical Trials Register).

Background The association between mitral valve prolapse (MVP) and sudden death remains controversial. We aimed to describe histopathological changes in individuals with autopsy-determined isolated MVP (iMVP) and sudden death and document cardiac arrest rhythm. Methods and Results The Australian National Coronial Information System database was used to identify cases of iMVP between 2000 and 2018. Histopathological changes in iMVP and sudden death were compared with 2 control cohorts matched for age, sex, height, and weight (1 group with noncardiac death and 1 group with cardiac death). Data linkage with ambulance services provided cardiac arrest rhythm for iMVP cases. From 77 221 cardiovascular deaths in the National Coronial Information System database, there were 376 cases with MVP. Individual case review yielded 71 cases of iMVP. Mean age was 49±18 years, and 51% were women. Individuals with iMVP had higher cardiac mass (447 g versus 355 g; P <0.001) compared with noncardiac death, but similar cardiac mass (447 g versus 438 g; P =0.64) compared with cardiac death. Individuals with iMVP had larger mitral valve annulus compared with noncardiac death (121 versus 108 mm; P <0.001) and cardiac death (121 versus 110 mm; P =0.002), and more left ventricular fibrosis (79% versus 38%; P <0.001) compared with noncardiac death controls. In those with iMVP and witnessed cardiac arrest, 94% had ventricular fibrillation. Conclusions Individuals with iMVP and sudden death have increased cardiac mass, mitral annulus size, and left ventricular fibrosis compared with a matched cohort, with cardiac arrest caused by ventricular fibrillation. The histopathological changes in iMVP may provide the substrate necessary for development of malignant ventricular arrhythmias.

Background and Objective: Publicly funded therapy for idiopathic pulmonary fibrosis (IPF) relies on percentage predicted values from pulmonary function testing, for example Australian patients must have a forced vital capacity ≥50% (%FVC), transfer factor of the lung for carbon monoxide ≥ 30% (%TLco) and forced expiratory volume in 1 s (FEV 1 )/FVC ratio > 0.7. Despite defined cut-off values, no jurisdiction prescribes a reference equation for use; multiple equations exist. We hypothesized that access to subsidized treatment varies depending on the chosen equation. The %FVC and %TLco from different commonly used reference equations across general respiratory patients, and IPF-specific patients, were compared., Methods: FVC and TLco measurements from a large general respiratory laboratory and the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR) database were analysed using multiple equations. Differences between %FVC and %TLco for each equation were calculated, with particular interest in classification of patients (%) at the threshold for subsidized treatment., Results: A total of 20 378 general respiratory database results were analysed. The %FVC ≥ 50% increased from 86% with the Roca equation to 96% with Quanjer (European Coal and Steal Community, ECSC) and %TLco≥30% increased from 91% with Paoletti to 98% with Thompson. However, overall increase in eligibility for subsidized treatment was modest, varying from 48.2% to 49.2%. A total of 545 AIPFR database results were analysed. The %FVC ≥ 50% increased from 73% with Roca to 94% with Quanjer (ECSC) and %TLco≥30% increased from 87% with Paoletti to 96% with Miller. Overall eligibility for subsidized treatment in the AIPFR group varied from 73.6% to 82.8% between surveyed interstitial lung disease (ILD) centres based entirely on the equation used., Conclusion: Substantial variability exists between reference equations, impacting access to subsidized treatment. Treating clinicians should be aware of this when assessing patients around public funding thresholds., (© 2019 Asian Pacific Society of Respirology.)

Background & Aims: Irisin, the cleaved extra-cellular fragment of the Fibronectin type III domain-containing protein 5 (FNDC5) is a myokine that is proposed to have favorable metabolic activity. We aimed to elucidate the currently undefined role of variants in the FNDC5 gene in non-alcoholic fatty liver disease (NAFLD)., Methods: We prioritized single nucleotide polymorphisms in FNDC5 on the basis of their putative biological function and identified rs3480 in the 3' untranslated region (3'UTR). We studied the association of rs3480 with liver disease severity and the metabolic profile of 987 Caucasian patients with NAFLD. Functional investigations were undertaken using luciferase reporter assays of the 3'UTR of human FNDC5, pyrosequencing for allele-specific expression of FNDC5 in liver, measurement of serum irisin, and bioinformatics analysis., Results: The rs3480 (G) allele was associated with advanced steatosis (OR 1.29; 95% CI 1.08-1.55; p = 0.004), but not with other histological features. This effect was independent but additive to PNPLA3 and TM6SF2. The rs3480 polymorphism influenced FNDC5 mRNA stability and the binding of miR-135a-5P. Compared with controls, hepatic expression of this microRNA was upregulated while FNDC5 expression was downregulated. Elevated serum irisin was associated with reduced steatosis, and an improved metabolic profile., Conclusions: Carriage of the FNDC5 rs3480 minor (G) allele is associated with more severe steatosis in NAFLD through a microRNA-mediated mechanism controlling FNDC5 mRNA stability. Irisin is likely to have a favorable metabolic impact on NAFLD., Lay Summary: Irisin is a novel protein produced mainly by muscle, which is known to be released into the circulation, with an unclear role in liver fat deposition. This study demonstrates that genetic variants in the gene encoding the irisin protein modulate the risk of liver fat in patients with fatty liver disease. Interestingly, these effects are independent of, but additive to those of other recently described genetic variants that contribute to liver fat. In functional studies, we have deciphered the detailed molecular mechanisms by which this genetic variant mediates its effects., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Cytomegalovirus (CMV) prophylaxis may prevent CMV indirect effects in renal transplant recipients. This study aimed to compare the efficacy of valganciclovir and valacyclovir prophylaxis for CMV after renal transplantation with the focus on chronic histologic damage within the graft., Methods: From November 2007 through April 2012, adult renal transplant recipients were randomized, in an open-label, single-center study, at a 1:1 ratio to 3-month prophylaxis with valganciclovir (n = 60) or valacyclovir (n = 59). The primary endpoint was moderate-to-severe interstitial fibrosis and tubular atrophy assessed by protocol biopsy at 3 years evaluated by a single pathologist blinded to the study group. The analysis was conducted in an intention-to-treat population., Results: Among the 101 patients who had a protocol biopsy specimen available, the risk of moderate-to-severe interstitial fibrosis and tubular atrophy was significantly lower in those treated with valganciclovir (22% versus 34%; adjusted odds ratio, 0.31; 95% confidence interval, 0.11-0.90; P = 0.032 by multivariate logistic regression). The incidence of CMV disease (9% versus 2%; P = 0.115) and CMV DNAemia (36% versus 42%; P = 0.361) were not different at 3 years., Conclusions: Valganciclovir prophylaxis, as compared with valacyclovir, was associated with a reduced risk of moderate-to-severe interstitial fibrosis and tubular atrophy in patients after renal transplantation., Trial Registration: Australian New Zealand Clinical Trials Registry ( ACTRN12610000016033 ). Registered on September 26, 2007.

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: There is limited knowledge on the extent and location of scarring that results from catheter ablation and its role in suppressing atrial fibrillation (AF). We examined the effect of atrial fibrosis and ablation-induced scarring on catheter ablation outcomes in AF., Methods: We conducted a prospective multicenter study that enrolled 329 AF patients presenting for catheter ablation. Delayed enhancement magnetic resonance imaging (DE-MRI) of the left atrium was obtained preablation. Scarring was evaluated in 177 patients with a DE-MRI scan obtained 90 days postablation. We evaluated residual fibrosis, defined as preablation atrial fibrosis not covered by ablation scar. The primary outcome was freedom from recurrent atrial arrhythmia., Results: In the analysis cohort of 177 patients, preablation fibrosis was 18.7 ± 8.7% of the atrial wall. Ablation aimed at pulmonary vein (PV) isolation was performed in 163 patients (92.1%). Ablation-induced scar averaged 10.6 ± 4.4% of the atrial wall. Scarring completely encircled all 4 PVs only in 12 patients (7.3%). Residual fibrosis was calculated at 15.8 ± 8.0%. At 325 days follow-up, 35% of patients experienced recurrent arrhythmia. Multivariable Cox proportional hazards models demonstrated that baseline atrial fibrosis (HR and 95% CIs) (1.09 [1.06-1.12], P < 0.001) and residual fibrosis (1.09 [1.05-1.13], P < 0.001) were associated with atrial arrhythmia recurrence, while PV encirclement and overall scar were not., Conclusions: Catheter ablation of AF targeting PVs rarely achieves permanent encircling scar in the intended areas. Overall atrial fibrosis present at baseline and residual fibrosis uncovered by ablation scar are associated with recurrent arrhythmia., (© 2015 Wiley Periodicals, Inc.)

Background: Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results., Methods: Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033., Findings: Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001)., Interpretation: A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years., Funding: Fonds Cancer, Belgium., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Abstract: Systemic sclerosis (SSc) is a rare and potentially severe connective-tissue disease, characterized by skin fibrosis and involvement of internal organs. Because of its rarity and heterogeneous clinical presentation, reliable epidemiological studies on SSc have been particularly difficult to carry out. SSc prevalence is estimated between 3 and 24 per 100,000 population and appears to be higher in North America and Australia as compared to Europe and Japan. Incidence estimates have significantly increased between the fifties and the eighties, but this could result from greater physician awareness of the disease and more reliable ascertainment methods. Risk factors for SSc include female sex and African origin. Reports of sporadic clusters of higher prevalence also suggest environmental risk factors. In particular, silica and solvents exposure has been associated with SSc by several rigorous case–control studies. The ten-year cumulative survival of SSc has improved significantly from 50% in the seventies to over 70% at the present time. Pulmonary fibrosis and pulmonary arterial hypertension are now the two main causes of death. Diffuse cutaneous forms, as well as cardiac, pulmonary, and renal involvement are independent risk factors for SSc-related mortality. [Copyright &y& Elsevier]

Pancreatitis and pancreatic cancer represent two major diseases of the exocrine pancreas. Pancreatitis exhibits both acute and chronic manifestations. The commonest causes of acute pancreatitis are gallstones and alcohol abuse; the latter is also the predominant cause of chronic pancreatitis. Recent evidence indicates that endotoxinemia, which occurs in alcoholics due to increased gut permeability, may trigger overt necroinflammation of the pancreas in alcoholics and one that may also play a critical role in progression to chronic pancreatitis (acinar atrophy and fibrosis) via activation of pancreatic stellate cells (PSCs). Chronic pancreatitis is a major risk factor for the development of pancreatic cancer, which is the fourth leading cause of cancer-related deaths in humans. Increasing attention has been paid in recent years to the role of the stroma in pancreatic cancer progression. It is now well established that PSCs play a key role in the production of cancer stroma and that they interact closely with cancer cells to create a tumor facilitatory environment that stimulates local tumor growth and distant metastasis. This review summarizes recent advances in our understanding of the pathogenesis of alcoholic pancreatitis and pancreatic cancer, with particular reference to the central role played by PSCs in both diseases. An improved knowledge of PSC biology has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in chronic pancreatitis and interrupting stellate cell-cancer cell interactions so as to retard cancer progression.

There are many conflicting opinions among health professionals and parents regarding care of the normal foreskin in young boys as well as the highly controversial subject of circumcision. Minor foreskin related complaints are very common in the first few years of life. Most of these can be managed with advice and reassurance, or with medical treatment alone. Circumcision is very rarely indicated in young boys, particularly under the age of 5 years. The issue of circumcision for non medical reasons, that is, religions, ethnic or personal, remains controversial.

This report describes toxoplasmosis lesions in Australian marsupials. Clinical signs, necropsy findings and histopathological changes are summarized for 43 macropods, two common wombats, two koalas, six possums, 15 dasyurids, two numbats, eight bandicoots and one bilby. Animals either died suddenly without clinical signs or exhibited signs associated with respiratory, neurological or enteric disease. At necropsy, many marsupials had no visible lesions. Where present, common necropsy findings included pulmonary congestion, oedema and consolidation, adrenal enlargement and reddening, haemorrhage and ulceration of stomach and small intestine, and lymphadenomegaly and splenomegaly. Microscopically, affected lungs showed interstitial pneumonia and macrophage accumulation. Myocardial, skeletal and smooth muscle necrosis and neutrophilic inflammation were common. Organs had focal necrosis and/or fibrosis and lymphoid infiltrates. Toxoplasma gondii tissue cysts were common in muscle and nervous tissue. Free tachyzoites were commonly present in areas of necrosis. Selected sections from four macropods, two koalas, two dasyurids, one wombat and one possum stained specifically with avidin-biotin complex and anti-Toxoplasma gondii serum.