Novel antiinflammatory biologics shaped by parasite-host coevolution.

Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host's immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions; however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm's excretory-secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory proteins. We successfully expressed 78 recombinant ES proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute colitis. After statistical filtering and ranking, 20 proteins conferred significant protection against various parameters of colitis. Lead candidates from distinct protein families, including annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS were identified. Representative proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory cytokine secretion by T cells from IBD patient colon biopsies. Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.

Nutrition adequacy, gastrointestinal, and hepatic function during extracorporeal membrane oxygenation in critically ill adults: A retrospective observational study.

AIMS: To identify clinical and biochemical markers associated with nutrition adequacy and gastrointestinal and liver dysfunction in adults on extracorporeal membrane oxygenation (ECMO). METHODS: A retrospective, observational, study was conducted at 2 centres in Australia. Adult patients who received ECMO from July 2011 to June 2015 were included. Mode of ECMO used, fluid balance, number of systemic inflammatory response syndrome (SIRS) criteria present, vasoactive-inotropic scores (VIS) and liver function tests (LFTs) were collected for the duration of ECMO until 7 days after ECMO cessation. Multiple regression models were used to determine if the collected variables were associated with nutrition adequacy. The mean LFTs during ECMO were also compared to mean LFTs post ECMO cessation. RESULTS: During the first 5 days of ECMO commencement, mean nutrition adequacy was 10% higher in the veno-venous (VV) ECMO group than in the veno-arterial (VA) group (95% confidence interval [CI], 2% to 17%). For every 5000 ml increase of fluid balance, an associated decrease in nutrition adequacy was observed (-8%, 95% CI: -15% to -2%). A doubling of bilirubin and VIS were associated with a mean reduction in nutrition adequacy of -5% (95% CI -8% to -2%) and - 2% (95% CI: -3% to -1%), respectively. CONCLUSIONS: In the first 5 days of ECMO commencement, higher nutrition adequacy was associated with the VV mode of ECMO and reduced nutrition adequacy with increased fluid balance, more vasopressor and inotropic support and raised bilirubin. Prospective investigation is required to confirm whether these associations have a causal relationship.

Changing prevalence of aetiological factors and comorbidities among Australians hospitalised for cirrhosis.

BACKGROUND: The rate of hospital admissions for cirrhosis increased 1.3-fold during 2008-2016 in Queensland. Alcohol misuse was a contributing factor for cirrhosis in 55% of admissions and 40% of patients had at least one comorbidity. AIMS: To examine the temporal change in aetiology of liver disease and presence of comorbidity in patients admitted with cirrhosis. METHODS: Population-based retrospective cohort study of all people treated in hospital for cirrhosis (10 254 patients) in Queensland during 2008-2016. Data were sourced from Queensland Hospital Admitted Patient Data Collection. RESULTS: The commonest aetiology was alcohol (49.5%), followed by cryptogenic (unspecified cirrhosis; 28.5%), hepatitis C virus (19.3%), non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) (4.8%) and hepatitis B virus (HBV) (4.3%). The prevalence of alcohol-related (P = 0.41) and hepatitis C virus (P = 0.08) remained stable between 2008-2010 and 2014-2016, that of NAFLD/NASH, cryptogenic and HBV-cirrhosis increased by 67% (P < 0.00001), 27% (P < 0.00001) and 20% (P = 0.00019), respectively; 41.1% of patients had at least one comorbidity. The prevalence of type 2 diabetes nearly doubled (from 13.7% to 25.4%; P < 0.00001) between 2008-2010 and 2014-2016. CONCLUSIONS: Alcohol misuse was the most important aetiology. The importance of NAFLD/NASH, cryptogenic and HBV-cirrhosis and the burden of comorbidity increased during 2008-2016. Ongoing alcohol misuse and the increasing prevalence of NAFLD/NASH, cryptogenic cirrhosis and comorbid type 2 diabetes among admissions for cirrhosis has implications for public health interventions to reduce the burden of unhealthy lifestyle and metabolic disorders.

Enablers and barriers for the provision of community-based HCV treatment: A case study of a real-world practice.

BACKGROUND: Although the availability of fully funded direct-acting antivirals (DAAs) and the eligibility of primary care providers (PCPs) to provide hepatitis C virus (HCV) have removed barriers related to access to hospital-based HCV treatment in Australia, there are still many barriers to the provision of HCV treatment in community settings. There is a lack of knowledge regarding the barriers to, and enablers of HCV treatment in community settings in Australia. This study aimed to identify barriers and enablers for the provision of community-based HCV treatment. METHODS: This study was a part of a mixed-method case study of the Cure-It programme. The programme was studied to better understand barriers and enablers experienced by stakeholders of such programmes. The programme is delivered through the Prince Charles Hospital in Brisbane, Australia, and aimed to improve access to HCV treatment in community settings. Data were collected using semi-structured interviews with 12 healthcare providers and nine patients between July and December 2018. Purposive sampling was used to ensure diverse views were captured. The interview transcripts were analysed using inductive thematic analysis. RESULTS: Ease of access to specialist support, easy and high value treatment, co-location with or providing other services and motivated patients enabled PCPs to be engaged with the Cure-It programme. Several interconnected factors related to patients' characteristics and health system acted synergistically to enable patients to initiate and complete treatment. These included a desire to remove HCV as a source of shame, having children, awareness of HCV consequences, access to DAAs for free, ease of access to general practices and drug and alcohol services, and access to a safe and enabling environment. The identified barriers were interconnected at the levels of patients, PCPs and primary care systems and acted synergistically to prevent patients and PCPs from becoming engaged with HCV treatment. PCPs' related barriers included a lack of knowledge, their perception of HCV as a specialist area and of patients with HCV as 'hard to manage' patients along with the practice preferences and priorities. Patients' related barriers included their socioeconomic characteristics, internalized stigma, perception of not being sick and lack of knowledge. Additionally, the unavailability of support for patients and existence of stigma in primary health care, along with poor communication between the hospital and primary care system, and the unavailability of FibroScan® in primary care discouraged PCPs and patients engagement specifically with the provision of community-based HCV treatment. CONCLUSION: Various strategies are needed to improve PCPs and patients' knowledge and awareness of HCV treatment. Training and support for PCPs need to be easy to access and should cover both clinical and social aspect of HCV. Connecting PCPs to other related services may improve PCPs' and patients' engagement with HCV treatment.

Effect of Midazolam in Addition to Propofol and Opiate Sedation on the Quality of Recovery After Colonoscopy: A Randomized Clinical Trial.

BACKGROUND: There is a concern that midazolam, when used as a component of sedation for colonoscopy, may impair cognition and prolong recovery. We aimed to identify whether midazolam produced short- and longer-term effects on multiple dimensions of recovery including cognition. METHODS: A 2-center double-blinded, placebo-controlled, parallel-group, randomized, phase IV study with a 1:1 allocation ratio was conducted in adults ≥18 years of age undergoing elective outpatient colonoscopy, with sufficient English language proficiency to complete the Postoperative Quality of Recovery Scale (PostopQRS). Participants were administered either midazolam (0.04 mg·kg) or an equivalent volume of 0.9% saline before sedation with propofol with or without an opiate. The primary outcome was incidence of recovery in the cognitive domain of the PostopQRS on day 3 after colonoscopy, which was analyzed using a χ test. Secondary outcomes included recovery in other domains of the PostopQRS over time, time to eye-opening, and hospital stay, and patient and endoscopist satisfaction. All hypotheses were defined before recruitment. RESULTS: During September 2015 to June 2018, 406 patients were allocated to either midazolam (n = 201) or placebo (n = 205), with one withdrawn before allocation. There was no significant difference in recovery in the cognitive domain of the PostopQRS on day 3 after colonoscopy (midazolam 86.8% vs placebo 88.7%, odds ratio, 0.838; 95% confidence interval [CI], 0.42-1.683; P= .625). Furthermore, there was no difference in recovery over time in the cognitive domain of the PostopQRS (P = .534). Overall recovery of the PostopQRS increased over time but was not different between groups. Furthermore, there were no differences between groups for nociceptive, emotive, activities-of-daily-living domains of the PostopQRS. Patient and endoscopist satisfaction were high and not different. There were no differences in time to eye-opening (midazolam 9.4 ± 12.8 minutes vs placebo 7.3 ± 0.7 minutes; P = .055), or time to hospital discharge (midazolam 103.4 ± 1.4 minutes vs placebo 98.4 ± 37.0 minutes; P = .516). CONCLUSIONS: The addition of midazolam 0.04 mg·kg as adjunct to propofol and opiate sedation for elective colonoscopy did not show evidence of any significant differences in recovery in the cognitive domain of the PostopQRS, overall quality of recovery as measured by the PostopQRS, or emergence and hospital discharge times. The use of midazolam should be determined by the anesthesiologist.

Clinical effectiveness, cost effectiveness and acceptability of community-based treatment of hepatitis C virus infection: A mixed method systematic review.

Several community-based models for treating hepatitis C virus (HCV) infection have been implemented to improve treatment accessibility and health outcomes. However, there is a lack of knowledge regarding how well these models achieve the desired goals. We conducted a mixed-method systematic review of quantitative and qualitative evidence about clinical effectiveness, cost effectiveness and acceptability of community-based HCV treatment models. Seventeen databases were researched for published and unpublished studies. Methodological quality was assessed using The Joanna Briggs Institute Critical Appraisal tools. Quantitative findings were synthesized in narrative form and qualitative findings were synthesized using meta-synthesis. Forty-two quantitative and six qualitative studies were included. No relevant cost effectiveness studies were found. Five categories of community-based models were identified: telehealth, integration of HCV and addiction services, integration of HCV and HIV services, integration of HCV and primary care, and implementation by a home care and health care management company. The range of reported outcomes included; end of treatment response: 48.7% to 96%, serious side effects: 3.3% to 27.8%, sustained virological response: 22.3% to 95.5%, relapse: 2.2% to 16.7%, and treatment completion: 33.4% to 100%. Inconsistent measures of uptake and adherence were used; uptake ranged from 8.3% to 92%, and 68.4% to 100% of patients received ≥80% of prescribed doses. Patient reported experiences included trusted and supportive care providers, safe and trusted services, easily accessible care, and positive psychological and behavioural changes. The clinical effectiveness and acceptability reported from the included studies are similar to or better than reported outcomes from systematic reviews of studies in tertiary settings. Studies of the cost effectiveness of community-based models for treating HCV are needed.

Sessile Serrated Adenomas in Young Patients may have Limited Risk of Malignant Progression.

GOALS: To provide preliminary evidence that sessile serrated adenomas (SSA) are low-risk polyps in young patients. BACKGROUND: SSAs are the dominant polyp of the serrated neoplasia pathway and as such are the precursor of up to 20% of colorectal carcinomas (CRC). Up to 90% of these cancers are expected to harbor a BRAF mutation. SSAs are being diagnosed with increasing frequency in young patients, placing a significant burden on colonoscopic services. Evidence to direct the surveillance intervals for these young patients is not available. STUDY: We utilized 2 patient cohorts comprising (1) a consecutive series of patients who underwent outpatient colonoscopy through a tertiary hospital and (2) a consecutive series of resection specimens for CRC processed through a gastrointestinal pathology service. The prevalence of SSAs by age was determined in the patients undergoing colonoscopy and compared with the ages of patients with BRAF mutated CRC in the pathology series. RESULTS: The prevalence of SSAs was similar irrespective of age. By comparison, BRAF mutated CRCs were very rare (3.8% of cases) in patients younger than 50 years of age and uncommon (9.3% of cases) in patients younger than 60 years of age, but increased to 39.8% in patients older than 80 years of age. CONCLUSIONS: These results suggest that SSAs develop at a young age, but have a prolonged dwell time and are unlikely to develop into cancer in patients younger than 60 years of age. These findings highlight the need for further targeted research to determine the most appropriate surveillance intervals for young patients with sporadic SSAs.

Safety and tolerability of experimental hookworm infection in humans with metabolic disease: study protocol for a phase 1b randomised controlled clinical trial.

BACKGROUND: Abdominal obesity and presence of the metabolic syndrome (MetS) significantly increase the risk of developing diseases such as Type 2 diabetes mellitus (T2DM) with escalating emergence of MetS and T2DM constituting a significant public health crisis worldwide. Lower prevalence of inflammatory and metabolic diseases such as T2DM in countries with higher incidences of helminth infections suggested a potential role for these parasites in the prevention and management of certain diseases. Recent studies confirmed the potential protective nature of helminth infection against MetS and T2DM via immunomodulation or, potentially, alteration of the intestinal microbiota. This Phase 1b safety and tolerability trial aims to assess the effect of inoculation with helminths on physical and metabolic parameters, immune responses, and the microbiome in otherwise healthy women and men. METHODS: Participants eligible for inclusion are adults aged 18-50 with central obesity and a minimum of one additional feature of MetS recruited from the local community with a recruitment target of 54. In a randomised, double-blind, placebo-controlled design, three groups will receive either 20 or 40 stage three larvae of the human hookworm Necator americanus or a placebo. Eligible participants will provide blood and faecal samples at their baseline and 6-monthly assessment visits for a total of 24 months with an optional extension to 36 months. During each scheduled visit, participants will also undergo a full physical examination and complete diet (PREDIMED), physical activity, and patient health (PHQ-9) questionnaires. Outcome measurements include tolerability and safety of infection with Necator americanus, changes in metabolic and immunological parameters, and changes in the composition of the faecal microbiome. DISCUSSION: Rising cost of healthcare associated with obesity-induced metabolic diseases urgently calls for new approaches in disease prevention. Findings from this trial will provide valuable information regarding the potential mechanisms by which hookworms, potentially via alterations in the microbiota, may positively influence metabolic health. TRIAL REGISTRATION: The protocol was registered on ANZCTR.org.au on 05 June 2017 with identifier ACTRN12617000818336. Alternatively, a Google search using the above trial registration number will yield a direct link to the trial protocol within the ANZCTR website.

Outcomes of a tertiary-based innovative approach to engage primary care providers in provision of hepatitis C treatment in community settings.

BACKGROUND: Australia is committed to eliminating the hepatitis C virus (HCV) by 2030. Despite regulations in Australia that enable the prescription of subsidised direct acting antiviral (DAA) by primary health care providers, the number of providers who treat patients for HCV remains low and this limits the prospect of HCV elimination. The Prince Charles Hospital, Brisbane, Australia, implemented an innovative program called Cure-It aimed at engaging primary care providers in community-based HCV treatment. This paper aims to describe initial experiences and short-term patient outcomes of this program. METHODS: A formative evaluation was conducted using program data for the period March 2016 to April 2018. Descriptive statistics were used to report the number of engaged primary care providers, patients' baseline characteristics, treatment plans, and treatment outcomes. RESULTS: Thirty primary care providers from different settings were engaged in HCV treatment. Among 331 patients eligible for community-based treatment, 315 (95.2%) commenced treatment, the completion rate was 92.4 and 66.5% achieved sustained virological response at 12 weeks (SVR12). The SVR12 had not been documented for 26.8% of patients. Among patients whose SVR12 was documented, 98.2% achieved SVR12. Only 1.3% of patients experienced treatment failure. CONCLUSION: A flexible tertiary-led model can improve primary care providers and patients' engagement with provision of HCV treatment. Tertiary centres need to play their role to improve the accessibility of HCV treatment through providing training and on-going support for primary care providers while enabling those providers to become more confident in providing treatment independently.

The use of modelling studies to inform planning of health services: case study of rapidly increasing endoscopy services in Australia.

BACKGROUND: Demand for gastrointestinal endoscopy in Australia is increasing as a result of the expanding national bowel cancer screening program and a growing, ageing population. More services are required to meet demand and ensure patients are seen within clinically recommended timeframes. METHODS: A discrete event simulation model was developed to project endoscopy waiting list outcomes for two large metropolitan health services encompassing 8 public hospitals in Australia. The model applied routinely collected health service data to forecast the impacts of future endoscopic demand over 5 years and to identify the level of service activity required to address patient waiting times and meet key policy targets. The approach incorporated evidence from the literature to produce estimates of cost-effectiveness by showing longer term costs and Quality Adjusted Life Years (QALYs) associated with service expansion. RESULTS: The modelling revealed that doing nothing would lead to the number of patients waiting longer than clinically recommended doubling across each health service within 5 years. A 38% overall increase in the number of monthly procedures available was required to meet and maintain a target of 95-98% of patients being seen within clinically recommended timeframes to the year 2021. This was projected to cost the funder approximately $140 million in additional activity over a 5 year period. Due to improved patient outcomes associated with timely intervention, it was estimated that the increased activity would generate over 22,000 additional QALYs across the two health services. This translated to an incremental cost-effectiveness ratio of $6467 and $5974 per QALY for each health service respectively. CONCLUSIONS: Discrete event simulation modelling provided a rational, data based approach that allowed decision makers to quantify the future demand for endoscopy services and identify cost-effective strategies to meet community needs.

Elements of community-based models for treating hepatitis C virus in supporting HCV elimination in Australia: A Delphi study.

BACKGROUND: A key to achieving the goal of hepatitis C virus (HCV) elimination is the provision of its treatment in community settings. This study aimed to identify the important organisational and operational elements of community-based models for treating HCV and their feasibility in the Australian context. METHODS: A Delphi study was conducted with 33 experts from Australia. The questionnaire included 13 elements drawn from the literature. Participants rated each element on a five-point Likert scale for importance and feasibility and suggested additional elements. Consensus was identified when the sum of categories 1 and 2 or 4 and 5 of the five-point Likert scale reached greater than or equal to 70%. RESULTS: Eight elements reached consensus in regard to importance including "Safe and enabling environment," "Training and support for healthcare providers," "Open referral policy," "Linkage with or providing outreach services," "Person-centred approach," "On-site screening and assessment," "Linkage or co-location with harm reduction services," and "Linkage or co-location with drug and alcohol services." At least 65% of participants agreed implementing elements of open referral policy, Training and support for healthcare providers, and Person-centred approach are usually or always/very feasible. For the other five elements, this was agreed to by a range of 15.2%-57.6% of participants. CONCLUSION: Successful community-based models for treating HCV in Australia are dependent on the integration and coordination of care and the support provided for both patients and healthcare providers. Substantial work is required across policy and health service planning to integrate these highly rated elements into Australian primary health care.

Upper gastrointestinal bleeding in neck of femur fracture patients: a single tertiary centre experience.

This study aimed to identify the incidence of perioperative acute upper gastrointestinal bleeding (UGIB) in our hip fracture patients; to evaluate the characteristics, management and clinical outcomes of these patients; and to explore risk factors and protective factors. Of the 1691 consecutive patients admitted for surgical management of hip fractures, 11 (0.65%) had UGIB and a further four patients for each case were selected as controls for evaluation of risk factors and protective factors. Pre-existing peptic ulcer disease was identified as a risk factor for acute UGIB (odds ratio 7.9; 95% confidence interval: 1.1-54.9). This study reported a very low incidence of UGIB in hip fracture patients. Despite being a high-risk population, timely endoscopic evaluation can be safely undertaken to optimise patient outcome. When risk factors such as history of peptic ulcer disease are present, additional precaution including gastro-protective agent and nutritional support should be undertaken.

High prevalence of sessile serrated adenomas in contemporary outpatient colonoscopy practice.

BACKGROUND: Sessile serrated adenomas (SSA) are the polyp precursor of 15-20% of colorectal carcinomas. There is debate about their prevalence and increasing discussion about the need for a serrated polyp detection rate as a quality indicator for colonoscopy. AIMS: To assess the prevalence of SSA at an outpatient gastroenterology service. METHODS: This is a retrospective study of an unselected consecutive series of patients who had an outpatient colonoscopy between April 2013 and May 2014. The colonoscopy reports were reviewed to identify age, gender, indication for procedure, completion, withdrawal time, adequacy of bowel preparation, number, size and location of polyps. The pathology of all polyps was centrally reviewed by a gastrointestinal pathologist. RESULTS: A total of 707 patients underwent colonoscopy within the study period. The mean age of the cohort was 58 years, and 50.6% were female. Polyp(s) were identified in 66.5% of patients. The SSA detection rate was 20.1%, and the adenoma detection rate was 48.0%. SSA detection was associated with longer withdrawal times. Conventional adenoma detection was associated with older age, male gender, longer withdrawal time and a positive faecal occult blood test result. CONCLUSION: SSA are highly prevalent in an unselected series of patients attending a gastroenterology outpatient department. Identifying and removing these polyps may help prevent interval colorectal carcinoma. This result may serve as a benchmark for a high-quality colonoscopy service.

Exploratory study into the unmet supportive needs of people diagnosed with cirrhosis in Queensland, Australia.

BACKGROUND: Many patients with cirrhosis follow complex medication and dietary regimens, and those with decompensated cirrhosis suffer debilitating complications. These factors impact activities of daily living and quality of life. AIMS: To explore the concerns and challenges of people with cirrhosis and their use of support services and to also describe health professionals' (HP) perspectives of patients' concerns. METHODS: This is a cross-sectional study at a tertiary liver clinic involving 50 patients and 54 HP. Data were collected using structured questionnaires. The study includes patients' report of their challenges/problems now that they have cirrhosis ('patient-volunteered concerns') and HP' report of patients' concerns. Both also ranked a list of 10 potential concerns. RESULTS: Patients were, on average, 58 years old (SD = 10.2), mostly male (78%), Caucasian (86%) and with compensated cirrhosis (60%). The patients' most common volunteered concerns related to managing symptoms, emotional issues and disease. Most ranked 'developing liver cancer' (79%), 'losing ability to do daily tasks for yourself' (76%), 'fear of dying' (64%) and 'fear of the unknown' (64%) as priority concerns. Regarding the use of support services, 24% of patients had accessed a dietician, 20% a pharmacist and 18% a psychologist. From the HP' perspective, the patients' most significant challenges related to managing disease (65%) and symptoms (48%), access to healthcare (56%) and information/knowledge (48%). CONCLUSIONS: Our findings demonstrate that cirrhosis (its symptoms, complications and treatment) is associated with significant concerns for patients. The discrepancies between the views of HP and patients suggest that we may not be measuring or addressing patients' needs appropriately.

Validation and analysis of prognostic scoring systems for critically ill patients with cirrhosis admitted to ICU.

INTRODUCTION: The number of patients admitted to ICU who have liver cirrhosis is rising. Current prognostic scoring tools to predict ICU mortality have performed poorly in this group. In previous research from a single centre, a novel scoring tool which modifies the Child-Turcotte Pugh score by adding Lactate concentration, the CTP + L score, is strongly associated with mortality. This study aims to validate the use of the CTP + L scoring tool for predicting ICU mortality in patients admitted to a general ICU with cirrhosis, and to determine significant predictive factors for mortality with this group of patients. This study will also explore the use of the Royal Free Hospital (RFH) score in this cohort. METHODS: A total of 84 patients admitted to the Glasgow Royal Infirmary ICU between June 2012 and Dec 2013 with cirrhosis were included. An additional cohort of 115 patients was obtained from two ICUs in London (St George's and St Thomas') collected between October 2007 and July 2009. Liver specific and general ICU scoring tools were calculated for both cohorts, and compared using area under the receiver operating characteristic (ROC) curves. Independent predictors of ICU mortality were identified by univariate analysis. Multivariate analysis was utilised to determine the most predictive factors affecting mortality within these patient groups. RESULTS: Within the Glasgow cohort, independent predictors of ICU mortality were identified as Lactate (p < 0.001), Bilirubin (p = 0.0048), PaO2/FiO2 Ratio (p = 0.032) and PT ratio (p = 0.012). Within the London cohort, independent predictors of ICU mortality were Lactate (p < 0.001), PT ratio (p < 0.001), Bilirubin (p = 0.027), PaO2/FiO2 Ratio (p = 0.0011) and Ascites (p = 0.023). The CTP + L and RFH scoring tools had the highest ROC value in both cohorts examined. CONCLUSION: The CTP + L and RFH scoring tool are validated prognostic scoring tools for predicting ICU mortality in patients admitted to a general ICU with cirrhosis.

Gene Variants Implicated in Steatotic Liver Disease: Opportunities for Diagnostics and Therapeutics.

Non-alcoholic fatty liver disease (NAFLD) describes a steatotic (or fatty) liver occurring as a consequence of a combination of metabolic, environmental, and genetic factors, in the absence of significant alcohol consumption and other liver diseases. NAFLD is a spectrum of conditions. Steatosis in the absence of inflammation is relatively benign, but the disease can progress into more severe forms like non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. NAFLD onset and progression are complex, as it is affected by many risk factors. The interaction between genetic predisposition and other factors partially explains the large variability of NAFLD phenotype and natural history. Numerous genes and variants have been identified through large-scale genome-wide association studies (GWAS) that are associated with NAFLD and one or more subtypes of the disease. Among them, the largest effect size and most consistent association have been patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) genes. Extensive in vitro and in vivo studies have been conducted on these variants to validate these associations. The focus of this review is to highlight the genetics underpinning the molecular mechanisms driving the onset and progression of NAFLD and how they could potentially be used to improve genetic-based diagnostic testing of the disease and develop personalized, targeted therapeutics.

Telomere biology disorder presenting acutely with pulmonary fibrosis and hepatopulmonary syndrome in a young adult male.

A 33-year-old man presented with acute dyspnoea and profound hypoxaemia, and had clubbing, greying of hair, orthodeoxia and fine inspiratory crackles. CT chest showed established pulmonary fibrosis in a usual interstitial pneumonia pattern. Additional investigations revealed a small patent foramen ovale, pancytopenia, and oesophageal varices and portal hypertensive gastropathy from liver cirrhosis. Telomere length testing demonstrated short telomeres (<1st percentile), confirming the diagnosis of a telomere biology disorder. An interstitial lung disease gene panel identified a pathogenic variant in TERT (c.1700C>T, p.(Thr567Met)) and a variant of uncertain significance in PARN (c.1159G>A, p.(Gly387Arg)). Combined lung and liver transplantation was deemed not suitable due to frailty and severe hepatopulmonary syndrome, and he died 56 days after presentation. Early recognition of the short telomere syndrome is important, and its multi-organ involvement poses challenges to management. Genetic screening may be important in younger patients with pulmonary fibrosis or in unexplained liver cirrhosis.

Changing Prevalence of Medication Use in People with Cirrhosis: A Retrospective Cohort Study Using Pharmaceutical Benefits Scheme Data.

BACKGROUND: Safe and appropriate use of medicines is essential to improve health outcomes in cirrhosis. However, little is known about the number and type of medicines dispensed to people with cirrhosis in Australia, as this predominantly occurs in the community. We aimed to characterise the prescriptions dispensed to people with cirrhosis and explore changes in the use of medication groups over time. METHODS: Pharmaceutical Benefits Scheme data between 1 January 2016 and 30 June 2020 was extracted for consenting CirCare participants (multi-site, prospective, observational study). Prescriptions dispensed from cirrhosis diagnosis until liver transplant or death were included. Safety classifications for dispensed medicines were defined using published evidence-based recommendations. The pattern of medication use was analysed in 6-monthly time intervals. Generalised estimating equations models were used to estimate the change in consumption of medicines over time. RESULTS: Five hundred twenty-two patients (mean age 60 years, 70% male, 34% decompensated at recruitment) were dispensed 89,615 prescriptions during the follow-up period, representing a median of 136 [interquartile range (IQR) 62-237] prescriptions and a median of 16 (IQR 11-23) unique medicines per patient (total n = 9306 medicines). The most commonly used medicines were proton pump inhibitors (PPIs) (dispensed at least once to 73% of patients), opioids (68%) and antibiotics (89%). Polypharmacy was prevalent, with 59-69% of observed participants in each time period dispensed five or more unique medicines. Prescription medication use increased over time (p < 0.001) independently of age, comorbidity burden and liver disease aetiology. The likelihood of taking PPIs, opioids, antidepressants and inhaled medicines also increased with each successive time period. Use of angiotensin therapies, metformin and statins differed over time between patients with compensated versus decompensated cirrhosis. General practitioners prescribed 69% of dispensed medicines, including a higher proportion of 'unsafe' and 'safety unknown' medicines compared with consultants/specialists (p < 0.001). CONCLUSIONS: Polypharmacy is common in people with cirrhosis and some medication groups may be overused. Pharmacovigilance is required and future medication safety efforts should target high-risk prescribing practices and promote medication rationalisation in the community.

Effect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes.

The reduced prevalence of insulin resistance and type 2 diabetes in countries with endemic parasitic worm infections suggests a protective role for worms against metabolic disorders, however clinical evidence has been non-existent. This 2-year randomised, double-blinded clinical trial in Australia of hookworm infection in 40 male and female adults at risk of type 2 diabetes assessed the safety and potential metabolic benefits of treatment with either 20 (n = 14) or 40 (n = 13) Necator americanus larvae (L3) or Placebo (n = 13) (Registration ACTRN12617000818336). Primary outcome was safety defined by adverse events and completion rate. Homoeostatic model assessment of insulin resistance, fasting blood glucose and body mass were key secondary outcomes. Adverse events were more frequent in hookworm-treated participants, where 44% experienced expected gastrointestinal symptoms, but completion rates were comparable to Placebo. Fasting glucose and insulin resistance were lowered in both hookworm-treated groups at 1 year, and body mass was reduced after L3-20 treatment at 2 years. This study suggests hookworm infection is safe in people at risk of type 2 diabetes and associated with improved insulin resistance, warranting further exploration of the benefits of hookworms on metabolic health.

Seasonal variability and meteorological factors: retrospective study of the incidence of pulmonary embolism from a large United kingdom teaching hospital.

BACKGROUND: Seasonal variations in the incidence of pulmonary embolism (PE) have been reported. It has been suggested that changes in meteorological factors may explain this variation. Previous studies have provided inconsistent results, possibly as a result of a small number of observations, in some studies and confounding factors. OBJECTIVE: To investigate whether there is a seasonal variation in the incidence of idiopathic PE and to investigate its relationship with atmospheric pressure, humidity, and temperature. METHODS: A large retrospective study was conducted. All confirmed cases of PE at our institution over a 9-year period were included, except for those patients with a major risk factor for PE. Meteorological data were obtained from a local weather station. Days when there was at least one episode of PE (event day) were compared with days when there were no episodes of PE (non-event day). RESULTS: There were a total of 640 episodes of PE. There was a statistically significant lower percentage of event days in spring (13.8%), compared with the rest of the year (18.3%) (P = .003). The incidence of PE was related to decreased atmospheric pressure and increased temperature. For atmospheric pressure the relationship was most significant for the mean atmospheric pressure for the 2 days preceding clinical presentation with PE (P = .02). For temperature the relationship was most significant for the mean temperature for the 5 days preceding clinical presentation with PE (P = .04). CONCLUSIONS: The results confirm the presence of seasonal variations in episodes of idiopathic PE and an association between decreased atmospheric pressure and increased temperature.