Metabolic-associated fatty liver disease and hepatocellular carcinoma: a prospective study of characteristics and response to therapy.

BACKGROUND AND AIM: The rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic-associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population. METHOD: Multicenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2-year period. RESULTS: Three hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the "mixed" group), and non-MAFLD (n = 179) were included in the study. Alcohol-associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD-HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self-reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate. CONCLUSION: Equal to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.

Serum interleukin-4 is elevated in clinical drug-induced liver injury.

BACKGROUND: Drug-induced liver injury (DILI) remains a challenging diagnosis due to an absence of specific biomarkers. DILI due to volatile anaesthetics (VA-DILI) is characterised by trifluoroacetyl and CYP2E1 antibodies, but may not be seen for weeks after injury. Interleukin-4 (IL-4) may be involved in the production of these antibodies and may serve as a clinically useful early biomarker of VA-DILI. AIM: To prospectively compare serum IL-4 levels between patients who develop VA-DILI and controls following exposure to the volatile anaesthetic. METHODS: A nested case-control study of patients exposed to VA during surgery was conducted. Thirteen DILI cases were identified from the original cohort, and 26 controls were matched according to age, sex and VA agent. Serum samples were collected before and 48-96 h after VA exposure, and analysed for IL-4 using quantitative enzyme-linked immunosorbent assay techniques. RESULTS: There was a statistically significant difference in serum IL-4 in post-VA samples between DILI cases and controls (control: 0.030 pg/mL, IQR: 0.030 - 0.030 pg/mL vs DILI: 0.044 pg/mL, IQR: 0.030 - 0.061 pg/mL; p = 0.039). A greater proportion of DILI cases had post-VA IL-4 levels above the assay lower limit of detection compared to controls (control: 23% vs DILI: 69%; p = 0.013). CONCLUSION: IL-4 is a potential biomarker of DILI. Clinical diagnosis and understanding of DILI disease mechanisms may be improved by further investigation of novel biomarkers, and this IL-4 signal in serum is important as proof of concept for prospective study designs.

Epidemiology and outcomes of primary sclerosing cholangitis: an Australian multicentre retrospective cohort study.

BACKGROUND AND AIMS: Little is known regarding the epidemiology and outcomes of patients with primary sclerosing cholangitis (PSC) in Australia. We, therefore, evaluated the epidemiology and clinical outcomes of PSC in a large cohort of Australian patients and compared these to the general population. METHODS: We conducted a multicentre, retrospective cohort study of PSC patients at nine tertiary liver centers across three Australian states, including two liver transplant centers. RESULTS: A total of 413 PSC patients with 3,285 person-years of follow-up were included. Three hundred and seventy-one (90%) patients had large duct PSC and 294 (71%) had associated inflammatory bowel disease. A total of 168 (41%) patients developed cirrhosis (including 34 at the time of PSC diagnosis) after a median of 15.8 (95% CI 12.4, NA) years. The composite endpoint of death or liver transplantation occurred in 49 (12%) and 78 (19%) patients, respectively, with a median transplant-free survival of 13.4 (95% CI 12.2-15) years. Compared to the general population, PSC accounted for a 240-fold increased risk of development of cholangiocarcinoma (CCA) and CCA-related death. CCA risk was increased with older age of PSC diagnosis, presence of dominant stricture and colectomy. Compared to same-aged counterparts in the general population, PSC patients who were diagnosed at an older age or with longer disease duration had reduced relative survival. CONCLUSION: In this large retrospective cohort study of PSC patients in Australia, increased age and time from diagnosis was associated with increased mortality and morbidity particularly from CCA and development of cirrhosis, necessitating need for liver transplant.

A multicentre, randomised controlled trial to compare the clinical and cost-effectiveness of Lee Silverman Voice Treatment versus standard NHS Speech and Language Therapy versus control in Parkinson's disease: a study protocol for a randomised controlled trial.

BACKGROUND: Parkinson's disease (PD) affects approximately 145,519 people in the UK. Speech impairments are common with a reported prevalence of 68%, which increase physical and mental demands during conversation, reliance on family and/or carers, and the likelihood of social withdrawal reducing quality of life. In the UK, two approaches to Speech and Language Therapy (SLT) intervention are commonly available: National Health Service (NHS) SLT or Lee Silverman Voice Treatment (LSVT LOUD®). NHS SLT is tailored to the individuals' needs per local practice typically consisting of six to eight weekly sessions; LSVT LOUD® comprises 16 sessions of individual treatment with home-based practice over 4 weeks. The evidence-base for their effectiveness is inconclusive. METHODS/DESIGN: PD COMM is a phase III, multicentre, three-arm, unblinded, randomised controlled trial. Five hundred and forty-six people with idiopathic PD, reporting speech or voice problems will be enrolled. We will exclude those with a diagnosis of dementia, laryngeal pathology or those who have received SLT for speech problems in the previous 2 years. Following informed consent and completion of baseline assessments, participants will be randomised in a 1:1:1 ratio to no-intervention control, NHS SLT or LSVT LOUD® via a central computer-generated programme, using a minimisation procedure with a random element, to ensure allocation concealment. Participants randomised to the intervention groups will start treatment within 4 (NHS SLT) or 7 (LSVT LOUD®) weeks of randomisation. PRIMARY OUTCOME: Voice Handicap Index (VHI) total score at 3 months. Secondary outcomes include: VHI subscales, Parkinson's Disease Questionnaire-39; Questionnaire on Acquired Speech Disorders; EuroQol-5D-5 L; ICECAP-O; resource utilisation; adverse events and carer quality of life. Mixed-methods process and health economic evaluations will take place alongside the trial. Assessments will be completed before randomisation and at 3, 6 and 12 months after randomisation. The trial started in December 2015 and will run for 77 months. Recruitment will take place in approximately 42 sites around the UK. DISCUSSION: The trial will test the hypothesis that SLT is effective for the treatment of speech or voice problems in people with PD compared to no SLT. It will further test whether NHS SLT or LSVT LOUD® provide greater benefit and determine the cost-effectiveness of both interventions. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number (ISRCTN) Registry, ID: 12421382. Registered on 18 April 2016.

Perinatal outcomes following mid trimester detection of isolated short foetal femur length.

BACKGROUND: Short foetal femur length (FL) is a normal variant but may also be a marker for disorders such as skeletal dysplasia, Trisomy 21 (T21), Turners syndrome, congenital infection (TORCH) and foetal growth restriction (FGR). AIM: Our aim was to review outcomes in our population following a diagnosis of isolated short FL (FL <5th centile) when detected at the time of mid trimester foetal anomaly scan (FAS). METHODS: All women within NHS Tayside who attended for routine mid trimester foetal anomaly scan at 18-21 weeks gestation (Range = 18+2-21+3 weeks) between November 2011 and June 2016 were included. Those who had an isolated FL <5th centile were identified using Viewpoint. Data relating to perinatal and childhood outcomes were obtained from local databases. RESULTS: 72 women were identified. The median maternal age was 30 years (range = 17-45 years). 39/72 (54.2%) women were primigravid. 41/72 (56.9%) women had Down's syndrome screening (DSS). 12/72 (16.7%) women were offered TORCH screens, none of which were positive for recent or current infection. Invasive testing was performed in 8/72 (11%) women; 1 had previously had first trimester chorionic villus sampling (CVS) for raised maternal age. 7 women had amniocentesis (1 prior to FAS for increased DSS risk). All those that had invasive testing had normal foetal karyotype. Median gestational age at delivery was 38 weeks (range = 26-41 weeks). 10/72 (13.9%) had genetic testing after birth, 6 were performed shortly after birth due to dysmorphic features. 4/72 (5.5%) had Trisomy 21 and 3 of these had VSD that had not been identified antenatally. For those with T21, 3 mothers had declined DSS and 1 had a low risk DSS result. Fifty out of seventy two (69.4%) babies had constitutionally short femurs. 13/72 (18%) had FGR and 3/72 (4.2%) had skeletal dysplasia. One baby had William's syndrome, one had Klinefelter syndrome and two had genetic deletions of uncertain significance. CONCLUSIONS: Knowledge of outcomes will enable better counselling for women with isolated short foetal femur. In our local population, more than two-thirds of the babies with isolated short femur will be normal. Women must, however, be informed of the potential for foetal aneuploidy and foetal skeletal dysplasia. In view of this, women should be offered invasive testing and follow-up ultrasound scans to assess the foetal skeleton. Furthermore isolated short foetal femur is a marker for FGR and all women with isolated short femur should be offered serial ultrasound scans to assess foetal growth and well-being in the third trimester.

Impact of viral hepatitis aetiology on survival outcomes in hepatocellular carcinoma: A large multicentre cohort study.

While HBV and HCV are risk factors for HCC, uncertainty exists as to whether these viral infections have prognostic significance in HCC. Thus, we compared the overall survival of patients with HBV, HCV and nonviral HCC, and evaluated whether the presence of HBV and HCV predicts patient outcomes. We conducted a multicentre study of HCC cases diagnosed at six Melbourne tertiary hospitals between Jan 2000-Dec 2014. Patient demographics, liver disease and tumour characteristics and patient outcomes were obtained from hospital databases, computer records and the Victorian Death Registry. Survival outcomes were compared between HBV, HCV and nonviral hepatitis cases and predictors of survival determined using Cox proportional hazards regression. There were 1436 new HCC cases identified including 776 due to viral hepatitis (HBV 235, HCV 511, HBV-HCV 30) and 660 from nonviral causes. The median survival of HBV, HCV and nonviral HCC patients was 59.1, 28.4 and 20.9 months, respectively (P<.0001). On multivariate analysis, independent risk factors for survival included HCC aetiology, gender, BCLC stage, serum AFP, total number and size of lesions, and serum creatinine and albumin. After adjusting for these and method of detection, HBV remained an independent predictor of improved overall survival when compared to both nonviral (HR 0.60%, 95% CI 0.35-0.98; P=.03) and HCV-related HCC (HR 0.51%, 95% CI 0.30-0.85; P=.01). In this large multicentre study, HBV is independently associated with improved overall survival compared with HCV and nonviral-related HCC. Further studies are needed to determine the underlying factor(s) responsible.

The changing place of liver biopsy in clinical practice: an audit of an Australian tertiary hospital.

Liver biopsy is an important tool in hepatology, with a role now generally limited to cases of diagnostic uncertainty. A retrospective audit performed at the Royal Melbourne Hospital aimed to identify the indications for liver biopsy and its impact on management. Ten per cent (20/195) of biopsies lacked a strong clinical indication, with hepatology involvement in only 8/20. We recommend prior hepatologist assessment to minimise unnecessary biopsies.

Seasonal influenza immunisation in Europe. Overview of recommendations and vaccination coverage for three seasons: pre-pandemic (2008/09), pandemic (2009/10) and post-pandemic (2010/11).

Since 2008, annual surveys of influenza vaccination policies, practices and coverage have been undertaken in 29 European Union (EU)/ European Economic Area (EEA) countries. After 2009, this monitored the impact of European Council recommendation to increase vaccination coverage to 75% among risk groups. This paper summarises the results of three seasonal influenza seasons: 2008/09, 2009/10 and 2010/11. In 2008/09, 27/29 countries completed the survey; in 2009/10 and 2010/11, 28/29 completed it. All or almost all countries recommended vaccination of older people (defined as those aged ≥50, ≥55, ≥59, ≥60 or ≥65 years), and people aged ≥6 months with clinical risk and healthcare workers. A total of 23 countries provided vaccination coverage data for older people, but only 7 and 10 had data for the clinical risk groups and healthcare workers, respectively. The number of countries recommending vaccination for some or all pregnant women increased from 10 in 2008/09 to 22 in 2010/11. Only three countries could report coverage among pregnant women. Seasonal influenza vaccination coverage during and after the pandemic season in older people and clinical groups remained unchanged in countries with higher coverage. However, small decreases were seen in most countries during this period. The results of the surveys indicate that most EU/EEA countries recommend influenza vaccination for the main target groups; however, only a few countries have achieved the target of 75% coverage among risk groups. Coverage among healthcare workers remained low.

Enhanced surveillance and investigation of coronavirus: what is required?

Following the discovery in September 2012 of 2 patients, both with links to the Eastern Mediterranean Region, with serious respiratory illness due to novel coronavirus, all countries have instigated surveillance and laboratory activities to detect further cases, with intensive case-contact investigations undertaken on laboratory confirmation of cases. A total of 30 cases, of whom 18 have died, and at least 3 clusters have been detected to date (1 cluster among health-care workers and another 2 clusters among family members). To date, transmission studies have shown a low risk of onward human transmission, with clinical presentation remaining severe for the majority. Many questions remain including the zoonotic source and geographical extent of infection. Surveillance has been extended to include clusters of cases or health-care workers with severe, undiagnosed respiratory illness regardless of travel history. Environmental studies, on-going surveillance and linked case-contact investigations will provide a critical role in answering some of these issues.

Public health investigations required for protecting the population against novel coronaviruses.

ABSTRACT There have been many laboratory-based investigations since the emergence of the novel coronaviruses in the autumn of 2012, but most of the parameters required for establishing scientifically the control measures that will protect against them have yet to be determined. Equally, the global distribution of the viruses in their animal reservoir has yet to be established. The experience of investigating and controlling another novel coronavirus, SARS, in 2003 shows how national and local investigations can come together as an international coalition and successfully avert epidemics. A menu of studies that need to be undertaken, especially in the countries experiencing transmission, is presented here.

Outbreak with a novel avian influenza A(H7N9) virus in China--scenarios and triggers for assessing risks and planning responses in the European Union, May 2013.

As part of the risk assessment and strategic planning related to the emergence of avian influenza A(H7N9) in China the European Centre for Disease Prevention and Control (ECDC) has considered two major scenarios. The current situation is the one of a zoonotic epidemic (Scenario A) in which the virus might be transmitted sporadically to humans in close contact with an animal reservoir. The second scenario is the movement towards efficient human to human transmission (a pandemic Scenario B). We identified epidemiological events within the different scenarios that would trigger a new risk assessment and a review of the response activities to implement in the European Union (EU). Further, we identified the surveillance activities needed to detect these events. The EU should prepare for importation of isolated human cases infected in the affected area, though this event would not change the level of public health risk. Awareness among clinicians and local public health authorities, combined with nationally available testing, will be crucial. A 'one health' surveillance strategy is needed to detect extension of the infection towards Europe. The emergence of a novel reassortant influenza A(H7N9) underlines that pandemic preparedness remains important for Europe.

Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case-control study.

Within the Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) project we conducted a multicentre case­control study in eight European Union (EU) Member States to estimate the 2011/12 influenza vaccine effectiveness against medically attended influenza-like illness (ILI) laboratory-confirmed as influenza A(H3) among the vaccination target groups. Practitioners systematically selected ILI / acute respiratory infection patients to swab within seven days of symptom onset. We restricted the study population to those meeting the EU ILI case definition and compared influenza A(H3) positive to influenza laboratory-negative patients. We used logistic regression with study site as fixed effect and calculated adjusted influenza vaccine effectiveness (IVE), controlling for potential confounders (age group, sex, month of symptom onset, chronic diseases and related hospitalisations, number of practitioner visits in the previous year). Adjusted IVE was 25% (95% confidence intervals (CI): -6 to 47) among all ages (n=1,014), 63% (95% CI: 26 to 82) in adults aged between 15 and 59 years and 15% (95% CI: -33 to 46) among those aged 60 years and above. Adjusted IVE was 38% (95%CI: -8 to 65) in the early influenza season (up to week 6 of 2012) and -1% (95% CI: -60 to 37) in the late phase. The results suggested a low adjusted IVE in 2011/12. The lower IVE in the late season could be due to virus changes through the season or waning immunity. Virological surveillance should be enhanced to quantify change over time and understand its relation with duration of immunological protection. Seasonal influenza vaccines should be improved to achieve acceptable levels of protection.

Epidemiology of hepatitis B-associated hepatocellular carcinoma in Victoria.

BACKGROUND: Chronic hepatitis B (HBV) and cirrhosis are major risk factors for hepatocellular carcinoma (HCC). The proportion and characteristics of cases with cirrhosis are not well documented. AIM: Our aim was to compare demographic, viral and tumour characteristics of HBV-associated HCC in an Australian cohort, in patients with and without cirrhosis. METHODS: Existing HCC databases at six Melbourne teaching hospitals were reviewed for cases associated with HBV. Patient demographics, HBV viral characteristics, presence of cirrhosis, serum alpha-fetoprotein and tumour size were assessed. Mode of diagnosis was recorded through surveillance or symptoms, and treatment was either palliative, percutaneous or surgical. RESULTS: We identified 197 cases of HBV-related HCC. The mean age was 57.9 ± 12.9 years; 83% were male, and 55.3% and 35.3% were of Asian and European descent respectively. Of 168 patient with available data, 146 (87%) had cirrhosis versus 22 (13%) without. Patients with cirrhosis tended to be older (median 60 vs 52 years, P = 0.078). Asian patients were more likely to have HCC without cirrhosis than Europeans (17% vs 6%, P = 0.04). There were no other differences identified between cirrhotic and non-cirrhotic patients. Thirty-four per cent of patients had tumours greater than 5 cm at diagnosis, and 47% were diagnosed after presenting with symptoms. Twelve patients with HBV-HCC were outside current screening guidelines. CONCLUSION: Most patients in Melbourne with HBV-associated HCC have cirrhosis. HCC characteristics in non-cirrhotic and cirrhotic patients were similar. The large number of patients detected through symptoms and with large tumours reinforces the need for vigilance in screening.

Public health investigations required for protecting the population against novel coronaviruses

There have been many laboratory-based investigations since the emergence of the novel coronaviruses in the autumn of 2012, but most of the parameters required for establishing scientifically the control measures that will protect against them have yet to be determined. Equally, the global distribution of the viruses in their animal reservoir has yet to be established. The experience of investigating and controlling another novel coronavirus, SARS, in 2003 shows how national and local investigations can come together as an international coalition and successfully avert epidemics. A menu of studies that need to be undertaken, especially in the countries experiencing transmission, is presented here

Enhanced surveillance and investigation of coronavirus: what is required?

Following the discovery in September 2012 of 2 patients, both with links to the Eastern Mediterranean Region, with serious respiratory illness due to novel coronavirus, all countries have instigated surveillance and laboratory activities to detect further cases, with intensive case contact investigations undertaken on laboratory confirmation of cases. A total of 30 cases, of whom 18 have died, and at least 3 clusters have been detected to date [1 cluster among health-care workers and another 2 clusters among family members]. To date, transmission studies have shown a low risk of onward human transmission, with clinical presentation remaining severe for the majority. Many questions remain including the zoonotic source and geographical extent of infection. Surveillance has been extended to include clusters of cases or health-care workers with severe, undiagnosed respiratory illness regardless of travel history. Environmental studies, on-going surveillance and linked case-contact investigations will provide a critical role in answering some of these issues

Influenza-related deaths--available methods for estimating numbers and detecting patterns for seasonal and pandemic influenza in Europe.

Two methodologies are used for describing and estimating influenza-related mortality: Individual-based methods, which use death certification and laboratory diagnosis and predominately determine patterns and risk factors for mortality, and population-based methods, which use statistical and modelling techniques to estimate numbers of premature deaths. The total numbers of deaths generated from the two methods cannot be compared. The former are prone to underestimation, especially when identifying influenza-related deaths in older people. The latter are cruder and have to allow for confounding factors, notably other seasonal infections and climate effects. There is no routine system estimating overall European influenza-related premature mortality, apart from a pilot system EuroMOMO. It is not possible at present to estimate the overall influenza mortality due to the 2009 influenza pandemic in Europe, and the totals based on individual deaths are a minimum estimate. However, the pattern of mortality differed considerably between the 2009 pandemic in Europe and the interpandemic period 1970 to 2008, with pandemic deaths in 2009 occurring in younger and healthier persons. Common methods should be agreed to estimate influenza-related mortality at national level in Europe, and individual surveillance should be instituted for influenza-related deaths in key groups such as pregnant women and children.

Influenza A(H1N1)pdm09 vaccination policies and coverage in Europe.

In August 2010 the Vaccine European New Integrated Collaboration Effort (VENICE) project conducted a survey to collect information on influenza A(H1N1)pdm09 vaccination policies and vaccination coverage in the European Union (EU), Norway and Iceland. Of 29 responding countries, 26 organised national pandemic influenza vaccination and one country had recommendations for vaccination but did not have a specific programme. Of the 27 countries with vaccine recommendations, all recommended it for healthcare workers and pregnant women. Twelve countries recommended vaccine for all ages. Six and three countries had recommendations for specific age groups in children and in adults, countries for specific adult age groups. Most countries recommended vaccine for those in new risk groups identified early in the pandemic such as morbid obese and people with neurologic diseases. Two thirds of countries started their vaccination campaigns within a four week period after week 40/2009. The reported vaccination coverage varied between countries from 0.4% to 59% for the entire population (22 countries); 3% to 68% for healthcare workers (13 countries); 0% to 58% for pregnant women (12 countries); 0.2% to 74% for children (12 countries). Most countries identified similar target groups for pandemic vaccine, but substantial variability in vaccination coverage was seen. The recommendations were in accordance with policy advice from the EU Health Security Committee and the World Health Organization.