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To assess the impact on diagnosis targets, cost, and cost-effectiveness of universal hepatitis B screening in Australia.Markov model simulation of disease and care cascade progression for people with chronic hepatitis B in Australia.Three scenarios were compared: 1. no change to current hepatitis B virus (HBV) testing practice; 2. universal screening strategy, with the aim of achieving the WHO diagnosis target by 2030 (90% of people with chronic hepatitis B diagnosed), based on opportunistic (general practitioner-initiated) screening for HBsAg; 3. universal screening strategy, and also ensuring that 50% of people with chronic hepatitis B are receiving appropriate clinical management by 2030.Projected care cascade for people with chronic hepatitis B, cumulative number of HBV-related deaths, intervention costs, and health utility (quality-adjusted life-years [QALYs] gained during 2020-2030). An incremental cost-effectiveness ratio (ICER) threshold (v scenario 1) of $50 000 per QALY gained was applied.Compared with scenario 1, 80 HBV-related deaths (interquartile range [IQR], 41-127 deaths) were averted during 2020-2030 in scenario 2, 315 HBV-related deaths (IQR, 211-454 deaths) in scenario 3. Scenario 2 cost $84 million (IQR, $41-106 million) more than scenario 1 during 2020-2030 (+8%), yielding an ICER of $104 921 (IQR, $49 587-107 952) per QALY gained. Scenario 3 cost $263 million (IQR, $214-316 million) more than scenario 1 during 2020-2030 (+24%), yielding an ICER of $47 341 (IQR, $32 643-58 200) per QALY gained. Scenario 3 remained cost-effective if the test positivity rate was higher than 0.35% or the additional costs per person tested did not exceed $4.02.Universal screening for hepatitis B will be cost-effective only if the cost of testing is kept low and people receive appropriate clinical management.

Background We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. Methods Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. Results Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2–8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. Conclusions Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.

In 2016, direct-acting antiviral (DAA) treatment for hepatitis C (HCV) became available through Australia's universal health care system, with the aim of HCV elimination. We report real-world effectiveness of DAA HCV treatment in Australia from a clinically well-informed cohort, enriched for cirrhosis and prior HCV treatment.3413 patients were recruited from 26 hospital liver clinics across Australia from February 2016 to June 2020. Clinical history and sustained viral response (SVR) were obtained from medical records and data linkage to the Australian Pharmaceutical Benefits Scheme. Factors associated with SVR were assessed by multivariable logistic regression (MVR).At recruitment, 32.2% had cirrhosis (72.9% Child Pugh class B/C), and 19.9% were treatment experienced. Of the 2,939 with data, 93.3% confirmed SVR. 137 patients received second-line therapy. Patients with cirrhosis had lower SVR rate (88.4 vs. 95.8%; p 0.001). On MVR, failure to achieve SVR was associated with Genotype 3 (adj-OR = 0.42, 95%CI 0.29-0.61), male gender (adj-OR = 0.49, 95%CI 0.31-0.77), fair/poor adherence (adj-OR = 0.52, 95%CI 0.28-0.94), cirrhosis (adj-OR = 0.57, 95%CI 0.36-0.88), FIB-4 3.25 (adj-OR = 0.52, 95%CI 0.33-0.83) and MELD score ≥ 20 (adj-OR = 0.25, 95%CI 0.08-0.80). Consistent results were seen in cirrhotic sub-analysis.Excellent SVR rates were achieved with DAAs in this real-world cohort of patients with chronic HCV infection. More advanced liver disease and clinician impression of poor adherence were associated with HCV treatment failure. Supports to improve liver fibrosis assessment skills for non-specialist DAA prescribers in the community and to optimize patient adherence are likely to enable more effective pursuit of HCV elimination in Australia.

Current guidelines recommend long-term nucleot(s)ide analogue (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB). However, disease remission has been described after stopping NA therapy, as well as HBsAg loss.We performed a prospective multi-centre cohort study of stopping NA therapy. Inclusion criteria were HBeAg-negative CHB, the absence of cirrhosis and HBVDNAlower limit of quantification for ≥18 months. We assessed virological and biochemical outcomes including HBsAg loss, as well as NA restart rates, over 96 weeks.In total, 110 patients [62% entecavir (ETV); 28% tenofovir (TDF), 10% other] were enrolled. Median age was 56 years, 57% were male, 85% were Asian, median baseline HBsAg level was 705 (214-2325) IU/ml. Virological reactivation occurred in 109/110 patients, median time to detection was 8 (4-12) weeks, and occurred earlier after stopping TDF versus ETV (median 4 vs. 12 weeks p 0.001). At week 96, 77 (70%) remained off-treatment, 65 (59%) had ALT2× ULN, 31 (28%) patients were in disease remission with HBVDNA2000 IU/ml plus ALT2× ULN and 7 (6%) patients had lost HBsAg. Baseline HBsAg ≤10 IU/ml was associated with HBsAg loss (6/9 vs. 1/101 p 0.001). ALT5× ULN occurred in 35 (32%); ALT flares were not associated with HBsAg loss. There were no unexpected safety issues.Virological reactivation was very common after stopping NA therapy and occurred earlier after stopping TDF versus ETV. The majority of patients had ALT2× ULN at week 96, but only one-third achieved disease remission and HBsAg loss was rare. Very low HBsAg levels at baseline were uncommon but predicted for HBsAg loss and disease remission.

PurposeTo determine the cost-effectiveness of annual renal imaging surveillance (RIS) in hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is associated with a 21% risk to age 70 years of RCC. Presentations with advanced renal cell cancer (RCC) are associated with poor outcomes whereas RIS detects early-stage RCC; however, evidence for the cost-effectiveness of RIS is lacking.MethodsWe developed a decision-analytic model to compare, at different age starting points (11 years, 18 years, 40 years, 60 years), the costs and benefits of lifetime contrast-enhanced renal MRI surveillance (CERMRIS) vs no surveillance in HLRCC. Benefits were measured in life-years gained (LYG), quality-adjusted life years (QALYs) and costs in British Pounds Sterling (GBP). Net monetary benefit (NMB) was calculated using a cost-effectiveness threshold of £20 000/QALY. One-way sensitivity and probabilistic analyses were also performed.ResultsIn the base-case 11-year age cohort, surveillance was cost-effective (Incremental_NMB=£3522 (95% CI −£2747 to £7652); Incremental_LYG=1.25 (95% CI 0.30 to 1.86); Incremental_QALYs=0.29 (95% CI 0.07 to 0.43)] at an additional mean discounted cost of £2185/patient (95% CI £430 to £4144). Surveillance was also cost-effective in other age cohorts and dominated a no surveillance strategy in the 40 year cohort [Incremental_NMB=£12 655 (95% CIs −£709 to £21 134); Incremental_LYG=1.52 (95% CI 0.30 to 2.26); Incremental_QALYs=0.58 (95% CI 0.12 to 0.87) with a cost saving of £965/patient (95% CI −£4202 to £2652).ConclusionAnnual CERMRI in HLRCC is cost-effective across age groups modelled.

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.

UNSTRUCTURED International deployment of remote monitoring and virtual care (RMVC) technologies would efficiently harness their positive impact on outcomes. Since Canada and the UK have similar populations, healthcare systems, and digital health landscapes, transferring digital health innovations between them should be relatively straightforward. Yet, examples of successful attempts are scarce. In a workshop, we identified six differences that may complicate RMVC transfer between Canada and the UK, and provide recommendations for addressing. These key differences include: 1) minority groups, (2) physical geography, (3) clinical pathways, (4) value propositions, (5) governmental priorities and support for digital innovation, (6) regulatory pathways. We detail four broad recommendations to plan for sustainability including: the need to formally consider how highlighted country-specific recommendations may impact RMVC and contingency planning to overcome challenges; the need to map which pathways are available as an innovator to support cross-country transfer; the need to report on and apply learnings from regulatory barriers and facilitators so that everyone may benefit; and explore existing guidance to successfully transfer digital health solutions while developing further guidance (e.g., extending the NASSS framework for cross-country transfer). Finally, we present an ecosystem readiness checklist. Considering these recommendations will contribute to successful international deployment and increased positive impact of RMVC technologies.

BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

Background & Aim Hepatitis B reactivation related to the use of immunosuppressive therapy remains a major cause of liver-related morbidity and mortality in hepatitis B endemic Asia-Pacific region. This clinical practice guidelines aim to assist clinicians in all disciplines involved in the use of immunosuppressive therapy to effectively prevent and manage hepatitis B reactivation. Methods All publications related to hepatitis B reactivation with the use of immunosuppressive therapy since 1975 were reviewed. Advice from key opinion leaders in member countries/administrative regions of Asian-Pacific Association for the study of the liver was collected and synchronized. Immunosuppressive therapy was risk-stratified according to its reported rate of hepatitis B reactivation. Recommendations We recommend the necessity to screen all patients for hepatitis B prior to the initiation of immunosuppressive therapy and to administer pre-emptive nucleos(t)ide analogues to those patients with a substantial risk of hepatitis and acute-on-chronic liver failure due to hepatitis B reactivation.

Goal The aim of this study was to evaluate current practice in gastric ulcer follow-up to establish diagnostic yield and predictors of malignancy. Background Repeat gastroscopy is routinely performed to confirm gastric ulcer healing and exclude malignancy. However, the incidence of malignancy at follow-up endoscopy is low, without consensus regarding case selection and timing. Study New gastric ulcers diagnosed on gastroscopy at 2 institutions in Australia were identified through keyword search of endoscopy reports over a 5-year period (2013 to 2017). Data collected included patient demographics, clinical presentation, and endoscopic and histologic findings from initial and subsequent gastroscopies. Results Of 795 patients, repeat gastroscopy was performed in 440 (55%). Malignancy was diagnosed in 52 (7%) with 83% identified at initial gastroscopy. Eight cancers were identified at repeat gastroscopy with malignancy yield of 2% (8/440). Three were diagnosed in patients with benign initial ulcer histology (3/286, 1%). One cancer was diagnosed during follow-up in a patient with benign histology but no repeat gastroscopy (1/286, 0.3%). Predictors of benign ulcers were absence of endoscopic suspicion [odds ratio (OR) 0.1 (0.03-0.13), P≤0.005], complete healing on repeat gastroscopy [OR 0.5 (0.34-0.70), P=0.036] and benign initial histology [OR 0.12 (0.43-0.90), P≤0.005]. Conclusions Seven percent of new gastric ulcers were malignant with most identified with biopsy on initial gastroscopy. Malignancy yield from follow-up gastroscopy was 2%. Diagnostic yield of endoscopic follow-up may be low in ulcers with benign appearance and adequate histology. However, current practice of repeat gastroscopy is warranted in the absence of patient-based and lesion-based predictors of malignancy.

Objectives To identify whether it is feasible to develop a mapping algorithm to predict presenteeism using multiattribute measures of health status. Methods Data were collected using a bespoke online survey in a purposive sample (n = 472) of working individuals with a self-reported diagnosis of Rheumatoid arthritis (RA). Survey respondents were recruited using an online panel company (ResearchNow). This study used data captured using two multiattribute measures of health status (EQ5D-5 level; SF6D) and a measure of presenteeism (WPAI, Work Productivity Activity Index). Statistical correlation between the WPAI and the two measures of health status (EQ5D-5 level; SF6D) was assessed using Spearman’s rank correlation. Five regression models were estimated to quantify the relationship between WPAI and predict presenteeism using health status. The models were specified based in index and domain scores and included covariates (age; gender). Estimated and observed presenteeism were compared using tenfold cross-validation and evaluated using Root mean square error (RMSE). Results A strong and negative correlation was found between WPAI and: EQ5D-5 level and WPAI (r = − 0.64); SF6D (r =− 0.60). Two models, using ordinary least squares regression were identified as the best performing models specifying health status using: SF6D domains with age interacted with gender (RMSE = 1.7858); EQ5D-5 Level domains and age interacted with gender (RMSE = 1.7859). Conclusions This study provides indicative evidence that two existing measures of health status (SF6D and EQ5D-5L) have a quantifiable relationship with a measure of presenteeism (WPAI) for an exemplar application of working individuals with RA. A future study should assess the external validity of the proposed mapping algorithms.

Background Advances in inflammatory bowel disease (IBD) monitoring, greater number of available treatments and a shift towards tight disease control, IBD care has become more dynamic with regular follow ups. Aims We assessed the impacts of the COVID‐19 pandemic on outpatient IBD patient care at a tertiary centre in Melbourne. More specifically, we assessed patient satisfaction with a telehealth model of care, failure to attend rates at IBD clinics and work absenteeism prior to and during the pandemic. Methods We conducted a retrospective, qualitative analysis to assess our aims through an online survey. We invited patients who attended an IBD outpatient clinic from April to June 2020 to participate. This study was conducted at a single, tertiary referral hospital in Melbourne. The key data points that we analysed were patient satisfaction with a telehealth model of care and the effect of telehealth clinics on work absenteeism. Results One hundred and nineteen (88.1%) patients were ‘satisfied’ or ‘very satisfied’ with the care received in the telehealth clinic. Eighty‐four (60.4%) patients reported needing to take time off work to attend a face‐to‐face appointment, compared to 29 (20.9%) patients who needed to take time off work to attend telehealth appointments (P

Background Prison-based hepatitis C treatment is safe and effective; however, many individuals are released untreated due to time or resource constraints. On community re-entry, individuals face a number of immediate competing priorities, and in this context, linkage to hepatitis C care is low. Interventions targeted at improving healthcare continuity after prison release have yielded positive outcomes for other health diagnoses; however, data regarding hepatitis C transitional care are limited. Methods We conducted a prospective randomized controlled trial comparing a hepatitis C care navigator intervention with standard of care for individuals released from prison with untreated hepatitis C infection. The primary outcome was prescription of hepatitis C direct-acting antivirals (DAA) within 6 months of release. Results Forty-six participants were randomized. The median age was 36 years and 59% were male. Ninety percent (n = 36 of 40) had injected drugs within 6 months before incarceration. Twenty-two were randomized to care navigation and 24 were randomized to standard of care. Individuals randomized to the intervention were more likely to commence hepatitis C DAAs within 6 months of release (73%, n = 16 of 22 vs 33% n = 8 of 24, P Conclusions Care navigation increased hepatitis C treatment uptake among untreated individuals released from prison. Public policy should support similar models of care to promote treatment in this high-risk population. Such an approach will help achieve hepatitis C elimination as a public health threat.

Gut function remains largely underinvestigated in undernutrition, despite its critical role in essential nutrient digestion, absorption and assimilation. In areas of high enteropathogen burden, alterations in gut barrier function and subsequent inflammatory effects are observable but remain poorly characterised. Environmental enteropathy (EE)—a condition that affects both gut morphology and function and is characterised by blunted villi, inflammation and increased permeability—is thought to play a role in impaired linear growth (stunting) and severe acute malnutrition. However, the lack of tools to quantitatively characterise gut functional capacity has hampered both our understanding of gut pathogenesis in undernutrition and evaluation of gut-targeted therapies to accelerate nutritional recovery. Here we survey the technology landscape for potential solutions to improve assessment of gut function, focussing on devices that could be deployed at point-of-care in low-income and middle-income countries (LMICs). We assess the potential for technological innovation to assess gut morphology, function, barrier integrity and immune response in undernutrition, and highlight the approaches that are currently most suitable for deployment and development. This article focuses on EE and undernutrition in LMICs, but many of these technologies may also become useful in monitoring of other gut pathologies.

Background: Primary prevention of cardiovascular disease (CVD) is guided by risk-prediction tools, but these rarely account for the risk of dying from other conditions (ie, competing mortality risk). In England and Wales, the recommended risk-prediction tool is QRISK2, and a new version (QRISK3) has been derived and internally validated. We aimed to externally validate QRISK3 and to assess the effects of competing mortality risk on its predictive performance.Methods: For this retrospective population cohort study, we used data from the Clinical Practice Research Datalink. We included patients aged 25-84 years with no previous history of CVD or statin treatment who were permanently registered with a primary care practice, had up-to-standard data for at least 1 year, and had linkage to Hospital Episode Statistics discharge and Office of National Statistics mortality data. We compared the QRISK3-predicted 10-year CVD risk with the observed 10-year risk in the whole population and in important subgroups of age and multimorbidity. QRISK3 discrimination and calibration were examined with and without accounting for competing risks.Findings: Our study population included 1 484 597 women with 42 451 incident CVD events (4·9 cases per 1000 person-years of follow-up, 95% CI 4·89-4·99), and 1 420 176 men with 53 066 incident CVD events (6·7 cases per 1000 person-years, 6·66-6·78), with median follow-up of 5·0 years (IQR 1·9-9·2). Non-CVD death rose markedly with age (0·4% of women and 0·5% of men aged 25-44 years had a non-CVD death vs 20·1% of women and 19·6% of men aged 75-84 years). QRISK3 discrimination in the whole population was excellent (Harrell's C-statistic 0·865 in women and 0·834 in men) but was poor in older age groups (Interpretation: QRISK3 performed well at the whole population level when ignoring competing mortality risk. The tool performed considerably less well in important subgroups, including older people and people with multimorbidity, and less well again after accounting for competing mortality risk.Funding: National Institute for Health Research.

The impact of hepatitis C cure with direct-acting antivirals (DAAs) on patient-reported outcomes (PROs) in community settings remains unclear. We aimed to assess changes in PROs over time and whether treatment was associated with sustained improved PROs in a cohort of people who inject drugs. This study is a sub-analysis of the Treatment and Prevention Study, a nurse-led trial where people who inject drugs and their injecting partners were recruited in a community setting, in Melbourne, Australia. Three participant groups were characterized: treatment, untreated and non-viremic (hepatitis C RNA negative at screening). PROs included assessment of health-related quality of life using the Short Form-8 (SF-8) Survey and life satisfaction using Personal Wellbeing Index (PWI). PROs were measured at baseline and every 12 weeks until week 84. Generalized estimating equations were used to measure whether treatment was associated with longitudinal PRO change. A total of 215 participants were included in this analysis. PWI scores were significantly higher at week 12 for both treatment group (p = 0.0309) and non-viremic group (p = 0.0437) compared to baseline. However, treatment was not associated with longitudinal change in PRO scores. In conclusion, we found DAA treatment did not significantly improve PRO scores compared to those not receiving treatment and without hepatitis C. The measures used in this study may not be sensitive enough to capture the hepatitis C specific improvements in quality of life that treatment affords or factors other than treatment may be influencing quality of life scores in this cohort.

Uveal melanoma (UM) metastasises in ~50% of patients, most frequently to the liver. Surveillance imaging can provide early detection of hepatic metastases; however, guidance regarding UM patient risk stratification for surveillance is unclear. This study compared sensitivity and specificity of four current prognostic systems, when used for risk stratification for surveillance, on patients treated at the Liverpool Ocular Oncology Centre (LOOC) between 2007–2016 (n = 1047). It found that the Liverpool Uveal Melanoma Prognosticator Online III (LUMPOIII) or Liverpool Parsimonious Model (LPM) offered greater specificity at equal levels of sensitivity than the American Joint Committee on Cancer (AJCC) system or monosomy 3 alone, and suggests guidance to achieve 95% sensitivity and 51% specificity (i.e., how to detect the same number of patients with metastases, while reducing the number of negative scans). For example, 180 scans could be safely avoided over 5 years in 200 patients using the most specific approach. LUMPOIII also offered high sensitivity and improved specificity over the AJCC in the absence of genetic information, making the result relevant to centres that do not perform genetic testing, or where such testing is inappropriate or fails. This study provides valuable information for clinical guidelines for risk stratification for surveillance in UM.

Background There is considerable interest in improving the education and care of women with inflammatory bowel disease (IBD) to improve pregnancy outcomes. Despite increased awareness, not all women with IBD have access to pregnancy-related education and the quality of counseling is variable. We aimed to assess the effectiveness of a simple educational intervention for improving pregnancy-related knowledge and to evaluate the effect of education on patient outcomes including anxiety, depression, and quality of life in women with IBD. Methods This prospective study of women with IBD who were pregnant or planning a pregnancy evaluated the effectiveness of a single gastroenterologist-led educational intervention in improving pregnancy-related knowledge, measured using the Crohn’s and Colitis Pregnancy Knowledge score 1 month postintervention. Secondary outcomes included the effect on anxiety and depression, quality of life, medication adherence, and patient satisfaction. Results One hundred women with IBD were recruited. Fifty percent were pregnant at the time of the intervention. Baseline knowledge scores were similar independent of the patients’ pregnancy status or whether they had previously received counseling from their gastroenterologist. Median Crohn’s and Colitis Pregnancy Knowledge scores postintervention (n = 82) were higher than preintervention scores (14/17 vs 10/17; P < 0.001). In addition, 32% of patients had poor knowledge at baseline (score ≤7/17), compared to only 5% after the intervention (P < 0.001). There was a significant improvement in total anxiety and depression and quality of life scores postintervention. Medication adherence and patient satisfaction were excellent. Conclusions Uptake of this gastroenterologist-led educational intervention has the potential to improve pregnancy knowledge, promote medication adherence, and enhance quality of life for women with IBD globally.

We evaluated the patterns of peripheral TLR signalling activity and the expression of TLRs and NK cell activation in a cohort of patients experiencing severe hepatitis flares after stopping NA therapy.Samples were collected longitudinally from CHB patients enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared to patients with normal ALT. PBMC were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46 and TREM-1 on monocytes, NK and NK-T cells was measured.17 patients with severe reactivation hepatitis flares were compared to 12 non-flare patients. Hepatitis flares were associated with increased activity of TLR 2-8 and TLR 9 signalling in PBMC at the time of peak flare compared to baseline. Hepatitis flares were also associated with upregulation of TLR2, and TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and non-flare patients.Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signalling on peripheral monocytes and TLR-2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.

The Holocene thermal maximum, a period of global warmth evident in early to mid-Holocene proxy reconstructions, is controversial. Most model simulations of the Holocene have not reproduced this warming, leading to a disagreement known as the Holocene Temperature Conundrum. Pollen records document the expansion of vegetation in the early and mid-Holocene African Sahara and Northern Hemisphere mid- and high latitudes, which has been overlooked in previous modeling studies. Here, we use time slice simulations of the Community Earth System Model to assess the impact of Northern Hemisphere vegetation change on Holocene annual mean temperatures. Our simulations indicate that expansion of Northern Hemisphere vegetation 9000 and 6000 years ago warms Earth’s surface by ~0.8° and 0.7°C, respectively, producing a better match with proxy-based reconstructions. Our results suggest that vegetation change is critical for modeling Holocene temperature evolution and highlight its role in driving a mid-Holocene temperature maximum.

Major gains in reducing the burden of hepatitis C are now possible because of the discovery of a cure. The prevention of premature deaths and increased workforce participation among people who are cured are likely to provide substantial indirect economic benefits. We developed an investment case for hepatitis C for the six WHO world regions, which, to our knowledge, is the first to consider both indirect and direct economic benefits in this context. Scaling up of testing and treatment to reach the 2030 WHO hepatitis C elimination targets was estimated to prevent 2·1 million (95% credible interval 1·3-3·2 million) hepatitis C-related deaths and 10 million (4-14 million) new hepatitis C virus infections globally between 2018 and 2030. This elimination strategy was estimated to cost US$41·5 billion (33·1-48·7 billion) in testing, treatment, and health care between 2018 and 2030 ($23·4 billion more than the status quo scenario of no testing or treatment scale up), with a global average of $885 (654-1189) per disability-adjusted life-year averted at 2030. Compared with the status quo scenario, the elimination scenario generated $46·1 billion (35·9-53·8 billion) in cumulative productivity gains by 2030. These indirect costs made elimination cost-saving by 2027, with a net economic benefit of $22·7 billion (17·1-27·9 billion) by 2030. This model shows that countries might be underestimating the true burden of hepatitis C and will benefit from investing in elimination.

Introduction: A patient is eligible for statins in England if they have a 10-year risk of cardiovascular disease >10%. We hypothesize that if statin discontinuation rates are high it may be better to delay statin initiation until patients are at a higher risk, to maximize the benefit of the drug. Methods: A four-state health state transition model was used to assess the optimal time to initiate statins after a risk assessment, in order to prevent the highest number of cardiovascular events, for a given risk profile (age, gender, risk) and adherence rate. A Clinical Practice Research Datalink dataset linked to Hospital Episodes Statistics and Office for National Statistics was used to inform the transition probabilities in this model, taking into account observed statin discontinuation and re-continuation patterns. Results: Our results suggest, if statins are initiated in a cohort of 50-year old men with a 10% 10-year risk, we prevent 4.78 events per 100 individuals. If we wait 10 years to prescribe, at which point 10-year risk scores are at 20%, we prevent 5.45 events per 100 individuals. If the observed discontinuation rate was reduced by a sixth, third or half in the same cohort, we would prevent 7.29, 9.01 or 10.22 events per 100 individuals. Conclusions: In certain scenarios, extra cardiovascular disease events could be prevented by delaying statin initiation beyond a risk of 10% until reaching a age (59 for men, 63 for women), based on statin discontinuation rates in England. The optimal time to initiate statins was driven by age, not by cardiovascular risk.

To achieve the elimination of the hepatitis C virus (HCV), sustained and sufficient levels of HCV testing is critical. The purpose of this study was to assess trends in testing and evaluate the effectiveness of strategies to diagnose people living with HCV. Data were from 12 primary care clinics in Victoria, Australia, that provide targeted services to people who inject drugs (PWID), alongside general health care. This ecological study spanned 2009–2019 and included analyses of trends in annual numbers of HCV antibody tests among individuals with no previous positive HCV antibody test recorded and annual test yield (positive HCV antibody tests/all HCV antibody tests). Generalised linear models estimated the association between count outcomes (HCV antibody tests and positive HCV antibody tests) and time, and χ2 test assessed the trend in test yield. A total of 44 889 HCV antibody tests were conducted 2009–2019; test numbers increased 6% annually on average [95% confidence interval (CI) 4–9]. Test yield declined from 2009 (21%) to 2019 (9%) (χ2P =

Background Dual sugar testing for gut permeability is time-consuming and complex. We explored the utility of fluorescein as a simple and inexpensive alternative method. Methods We used a confocal laser endomicroscopy probe placed at the fingertip of participants who had ingested sodium fluorescein to measure the fluorescence at various time points. Results In 10 patients with diarrhoea, but not in 10 controls, fluorescence was detected quickly. By 6 min fluorescence was detected in all diarrhoea patients but only 1 control (p=0.0004). After 15 min there was no difference between the groups. Conclusions This simple oral fluorescein test may be useful to study gut permeability in low-resource settings.

Point-of-care (POC) diagnostics overcome barriers to conventional hepatitis C (HCV) testing in people who inject drugs. This study assessed impact on hepatitis C treatment uptake of POC HCV testing in needle and syringe exchange programs (NSPs). Rapid EC was a single-arm interventional pilot study of HCV POC testing conducted in three inner-city community clinics with NSPs. Twelve months after the POC testing, a retrospective medical record and Pharmaceutical Benefits Scheme audit was performed to determine the number of HCV RNA-positive participants who were prescribed HCV treatment. 70 HCV RNA-positive Rapid EC study participants were included. 44 (63%) were prescribed DAAs; 26 (59%) completed treatment and 15 (34%) had SVR testing, all of whom were cured. Age ≥ 40 years (aOR 3.45, 95% CI 1.10-11.05, p = .03) and secondary school education (aOR 5.8, 95% CI 1.54-21.80, p = .009) had higher likelihood of being prescribed DAAs, whereas homelessness was inversely associated with prescription of DAAs (aOR 0.30, 95% CI 0.09-1.04, p = .057). Median time to receive a DAA script from date of diagnosis was seven days (IQR 0 to 14 days), and time to filling the DAA prescription was 2 days (IQR 0-12 days). In conclusion, provision of POC testing through NSPs was effective for linking new clients to HCV treatment and reduced the time to treatment. Further studies are needed to define the most cost-effective use of POC testing in models of care for people who inject drugs to increase HCV treatment uptake.

Conventional pull-through percutaneous endoscopic gastrostomy (PEG) risks infection and tumour implantation in head and neck cancers. Endoscopically inserted direct gastrostomy has lower rates of complications but is underutilised.To describe the endoscopic steps for direct gastrostomy insertion and review our single-centre experience to assess the technical feasibility and safety.Patients who underwent endoscopic direct gastrostomy insertion between December 2016 and June 2021 were included. A 24Fr introducer kit for gastrostomy feeding tube (Avanos Healthcare, Australia) was used. Patient and tumour characteristics, procedural data and 30-day outcomes were recorded.Thirty patients underwent direct PEG insertion (mean age 64 years and 24 male). All were planned for or currently undergoing radiotherapy. Twenty-six (87%) of 30 cases were performed under conscious sedation over a median procedure time of 21 min (interquartile range 11 min). No tumour seeding was seen, and one case of PEG-site infection was observed.Direct PEG is safe and effective and should be considered for patients with aerodigestive tract cancer in need of nutritional support.

The prevalence of hepatitis B virus (HBV) infection in Australia is nearly 1%. In certain well defined groups the prevalence is far greater, yet an estimated 27% of people living with HBV infection remain undiagnosed. Appropriate screening improves detection, increases opportunity for treatment, and ultimately reduces the significant morbidity and mortality associated with the development of liver fibrosis and hepatocellular carcinoma (HCC).This statement highlights important aspects of HBV infection management in Australia. There have been recent changes in nomenclature and understanding of natural history, as well as a newly defined upper limit of normal for liver tests that determine phase classification and threshold for antiviral treatment. As the main burden of hepatitis B in Australia is within migrant and Indigenous communities, early identification and management of people living with hepatitis B is essential to prevent adverse outcomes including liver cancer and cirrhosis.These recommendations aim to raise awareness of the current management of hepatitis B in Australia. Critically, the timely identification of individuals living with hepatitis B, and where appropriate, commencement of antiviral therapy, can prevent the development of cirrhosis, HCC and mother-to-child transmission as well as hepatitis B reactivation in immunocompromised individuals. Recognising patient and viral factors that predispose to the development of cirrhosis and HCC will enable clinicians to risk-stratify and appropriately implement surveillance strategies to prevent these complications of hepatitis B.

Background People with cystic fibrosis are susceptible to pulmonary infection with Pseudomonas aeruginosa. This may become chronic and lead to increased mortality and morbidity. If treatment is commenced promptly, infection may be eradicated through prolonged antibiotic treatment. Objective To compare the clinical effectiveness, cost-effectiveness and safety of two eradication regimens. Design This was a Phase IV, multicentre, parallel-group, randomised controlled trial. Setting Seventy UK and two Italian cystic fibrosis centres. Participants Participants were individuals with cystic fibrosis aged > 28 days old who had never had a P. aeruginosa infection or who had been infection free for 1 year. Interventions Fourteen days of intravenous ceftazidime and tobramycin or 3 months of oral ciprofloxacin. Inhaled colistimethate sodium was included in both regimens over 3 months. Consenting patients were randomly allocated to either treatment arm in a 1 : 1 ratio using simple block randomisation with random variable block length. Main outcome measures The primary outcome was eradication of P. aeruginosa at 3 months and remaining free of infection to 15 months. Secondary outcomes included time to reoccurrence, spirometry, anthropometrics, pulmonary exacerbations and hospitalisations. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who had received at least one dose of any of the study drugs. Cost-effectiveness analysis explored the cost per successful eradication and the cost per quality-adjusted life-year. Results Between 5 October 2010 and 27 January 2017, 286 patients were randomised: 137 patients to intravenous antibiotics and 149 patients to oral antibiotics. The numbers of participants achieving the primary outcome were 55 out of 125 (44%) in the intravenous group and 68 out of 130 (52%) in the oral group. Participants randomised to the intravenous group were less likely to achieve the primary outcome; although the difference between groups was not statistically significant, the clinically important difference that the trial aimed to detect was not contained within the confidence interval (relative risk 0.84, 95% confidence interval 0.65 to 1.09; p = 0.184). Significantly fewer patients in the intravenous group (40/129, 31%) than in the oral group (61/136, 44.9%) were hospitalised in the 12 months following eradication treatment (relative risk 0.69, 95% confidence interval 0.5 to 0.95; p = 0.02). There were no clinically important differences in other secondary outcomes. There were 32 serious adverse events in 24 participants [intravenous: 10/126 (7.9%); oral: 14/146 (9.6%)]. Oral therapy led to reductions in costs compared with intravenous therapy (–£5938.50, 95% confidence interval –£7190.30 to –£4686.70). Intravenous therapy usually necessitated hospital admission, which accounted for a large part of this cost. Limitations Only 15 out of the 286 participants recruited were adults – partly because of the smaller number of adult centres participating in the trial. The possibility that the trial participants may be different from the rest of the cystic fibrosis population and may have had a better clinical status, and so be more likely to agree to the uncertainty of trial participation, cannot be ruled out. Conclusions Intravenous antibiotics did not achieve sustained eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. Although there were fewer hospitalisations in the intravenous group during follow-up, this confers no advantage over the oral therapy group, as intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis. Future work Future research studies should combine long-term follow-up with regimens to reduce reoccurrence after eradication. Trial registration Current Controlled Trials ISRCTN02734162 and EudraCT 2009-012575-10. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 65. See the NIHR Journals Library website for further project information.

BACKGROUND: Point‐of‐care ultrasound (POCUS), performed by a gastroenterologist, provides safe and convenient imaging allowing for immediate clinical decision in Crohn's disease. The minimum training required to gain competency, its accuracy and clinical utility requires evaluation. METHODS: In this pilot study, Crohn's disease activity and extent were assessed using POCUS (performed by a single gastroenterologist following the completion of 200 supervised scans), magnetic resonance enterography (MRE) and ileo‐colonoscopy. The presence of complications was assessed by POCUS and MRE. Accuracy of POCUS was analysed with respect to MRE and ileo‐colonoscopy. Agreement between modalities was assessed using kappa coefficient. RESULTS: Forty‐two patients had a POCUS paired with MRE. Thirty‐eight patients had a POCUS paired with ileo‐colonoscopy. When compared to MRE, POCUS was accurate in the assessment of disease activity (sensitivity 87.5%, specificity 61.1%, ROC 0.74), extent (sensitivity 77.8%, specificity 83.3%, ROC 0.81) and complications (sensitivity 85.7%, specificity 94.3%, ROC 0.90). Agreement between POCUS and MRE was moderate (kappa estimates 0.50, P