Pre-diagnostic plasma inflammatory proteins and risk of hepatocellular carcinoma in three population-based cohort studies from the United States and the United Kingdom.

Previous studies suggest a role for inflammation in hepatocarcinogenesis. However, no study has comprehensively evaluated associations between circulating inflammatory proteins and risk of hepatocellular carcinoma (HCC) among the general population. We conducted a nested case-control study in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) with 56 pairs of incident HCC cases and controls. External validation was performed in the UK Biobank (34 HCC cases and 48,471 non-HCC controls). Inflammatory protein levels were measured in pre-diagnostic plasma using the Olink® Inflammation Panel. We used conditional logistic regression to calculate multivariable odds ratios (ORs) with 95% confidence intervals (CIs) for associations between a 1-standard deviation (SD) increase in biomarker levels and HCC risk, considering a statistically significant threshold of false discovery rate (FDR)-adjusted p < .05. In the NHS/HPFS, among 70 analyzed proteins with call rates >80%, 15 proteins had significant associations with HCC risk (pFDR < .05). Two proteins (stem cell factor, OR per SD = 0.31, 95% CI = 0.16-0.58; tumor necrosis factor superfamily member 12, OR per SD = 0.51, 95% CI = 0.31-0.85) were inversely associated whereas 13 proteins were positively associated with risk of HCC; positive ORs per SD ranged from 1.73 for interleukin (IL)-10 to 2.35 for C-C motif chemokine-19. A total of 11 proteins were further replicated in the UK Biobank. Seven of the eight selected positively associated proteins also showed positive associations with HCC risk by enzyme-linked immunosorbent assay, with ORs ranging from 1.56 for IL-10 to 2.72 for hepatocyte growth factor. More studies are warranted to further investigate the roles of these observed inflammatory proteins in HCC etiology, early detection, risk stratification, and disease treatment.

Statin use in cirrhosis and its association with incidence of portal vein thrombosis.

BACKGROUND AND AIM: Statin use has shown a reduction in hepatic decompensation and portal hypertension. Its association with portal vein thrombosis (PVT) incidence is unknown. We aim to compare the incidence of PVT in patients with and without statin use. METHODS: We excluded patients with a history of hepatocellular cancer, liver transplants, Budd-Chiari syndrome, and intra-abdominal malignancies. Patients with cirrhosis were followed from their first hepatologist clinical encounter (January 1, 2016, to January 31, 2021) for 180 days to determine PVT incidence. We tested the association of statin use with PVT using 1:1 propensity score (PS) matching and Cox proportional hazard regression. RESULTS: We analyzed 2785 patients with cirrhosis (mean age:61.0 ± 12.3 years, 44.3% female, 63.8% White, mean MELD-Na score:11.7 ± 6.1, and statin use:23.1%). A total of 89 patients developed PVT during the follow-up, which was lower in patients with statin use as compared to no statin use (1.3% vs 3.8%, P = 0.001, unadjusted HR:0.28, 95% CI: 0.13-0.62, P = 0.001). After matching for demographics, comorbidities, and hepatic decompensation events, patients with statin use had a lower risk of developing PVT in 180-day follow-up as compared to those without statin use (HR:0.24, 95% CI: 0.10-0.55, P = 0.001). Subgroup analysis showed that statin use was associated with lower PVT incidence in non-NASH (HR: 0.20, 95% CI: 0.07-0.54, P = 0.002) and decompensated cirrhosis (HR: 0.12, 95% CI:0.03-0.53, P = 0.005) than no statin use. CONCLUSION: PVT incidence was lower in decompensated cirrhosis patients with statin use than in those with no statin use. However, this finding needs to be further tested in randomized control trials.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

Impact of an evidence-based bundle on incontinence-associated dermatitis prevalence in hospital patients: A quasi-experimental translational study.

The study aimed to evaluate the effect of an intervention on the prevalence and severity of incontinence-associated dermatitis (IAD) in six hospitals in one state in Australia. This quasi-experimental pre-and post-study, conducted in 18 wards, was part of a larger implementation science study on incontinence-associated dermatitis. Skin and incontinence assessments were conducted on patients during February and March 2020 (pre-intervention) and July and August 2021 (post-intervention). The intervention comprised continence assessment and management, an education brochure for patients, family and caregivers on IAD, the Ghent Global IAD Categorisation Tool (GLOBIAD) and a skin care regime with patient skin protection measures (three-in-one barrier cream cloths, minimisation of bed protection layers, use of appropriate continence aid). A total of 1897 patients were assessed (pre-intervention = 964, post-intervention = 933). A total of 343 (35.6%) pre-intervention patients and 351 (37.6%) post-intervention patients had incontinence. The prevalence of hospital-acquired IAD was 6.71% in the pre-intervention group and 4.27% in the post-intervention group; a reduction of 36.3% (p = 0.159) despite higher patient acuity, prevalence of double incontinence and the COVID-19 pandemic in the post-intervention group compared with the pre-intervention group. Our multisite best practice IAD prevention and treatment intervention was able to reduce the prevalence and severity of hospital-acquired IAD, suggesting enduring effectiveness of the intervention.

Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis.

BACKGROUND AND AIMS: Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation. APPROACH AND RESULTS: We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z. CONCLUSIONS: Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.

Steroid Use and Risk of Nonalcoholic Fatty Liver Disease in Patients With Inflammatory Bowel Disease: Systematic Review and Meta-analysis.

GOALS: We sought to evaluate the association of steroids with nonalcoholic fatty liver disease (NAFLD) among patients with inflammatory bowel disease (IBD). BACKGROUND: Patients with IBD are at increased risk of NAFLD. Steroids may have a role in the pathogenesis of NAFLD. STUDY: We searched MEDLINE (through PubMed) and Embase for studies from inception to July 2021. We included published interventional and observational studies of adults 18 years or older with ulcerative colitis or Crohn's disease. We reported odds ratios, 95% confidence intervals, and generated forest plots. A random effects model generated a summary effect estimate. Publication bias was assessed by funnel plot and Egger's test. Study quality was examined using modified Newcastle-Ottawa scale (NOS) and Agency for Healthcare Research and Quality (AHRQ). RESULTS: A total of 12 observational studies with 3497 participants were included. NAFLD was identified in 1017 (29.1%) patients. The pooled odds ratio for the development of NAFLD in steroid users versus non-users was 0.87 (95% confidence interval: 0.72-1.04). There was no significant heterogeneity between studies ( I ²=0.00%, P =0.13). No publication bias was detected by funnel plot or Egger's test ( P =0.24). Findings were consistent among subgroup analyses stratified by study quality. CONCLUSION: In this meta-analysis, steroids were not associated with NAFLD in patients with IBD. Steroids may not need to be withheld from patients with IBD for the purposes of preventing NAFLD. Additional prospective studies that systematically document steroid exposure and important confounders among patients with IBD are warranted.

Type 2 diabetes complications are associated with liver fibrosis independent of hemoglobin A1c.

INTRODUCTION AND OBJECTIVES: The association between type 2 diabetes, non-alcoholic fatty liver disease, and liver fibrosis is well established, but it is unknown whether complications of type 2 diabetes influence fibrosis levels. We defined the complications of type 2 diabetes by the presence of diabetic nephropathy, retinopathy, or neuropathy and aimed to evaluate their association with the degree of liver fibrosis measured by the fibrosis-4 (FIB-4) index. MATERIALS AND METHODS: This is a cross-sectional study evaluating the association of type 2 diabetes complications with liver fibrosis. A total of 2389 participants were evaluated from a primary care practice. FIB-4 was evaluated as a continuous and categorical measure using linear and ordinal logistic regression. RESULTS: Patients with complications were older, had higher hemoglobin A1c, and a higher median FIB-4 score (1.34 vs. 1.12, P<0.001). On adjusted analysis, type 2 diabetes complications were associated with higher fibrosis by continuous FIB-4 score (Beta-coefficient: 0.23, 95% confidence interval [CI]: 0.004-1.65) and demonstrated increased odds of fibrosis by categorical FIB-4 score (odds ratio [OR]: 4.48, 95% CI: 1.7-11.8, P=0.003), independent of hemoglobin A1c level. CONCLUSIONS: The presence of type 2 diabetes complications is associated with the degree of liver fibrosis, independent of hemoglobin A1c level.

Blepharospasm Secondary to Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson Disease: Clinical Characteristics and Management Outcomes.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for patients with motor symptoms of Parkinson disease but can be complicated by disabling blepharospasm and apraxia of eyelid opening (ALO). Currently, there is no clear consensus on optimal management, and addressing these issues is further hindered by systemic morbidity and resistance to treatments. We aim to describe the different phenotypes of these eyelid movement disorders, to report our management approach and patient responses to treatment. METHODS: A retrospective case series of all patients with blepharospasm/ALO secondary to STN-DBS that were treated at a tertiary center between 2011 and 2020. Data collected included date of Parkinson diagnosis, date of DBS surgery, date of development of blepharospasm/ALO symptoms, STN-DBS stimulation settings, and treatment given. Patients' symptoms before and after treatment were measured using the blepharospasm disability index and Jankovic Rating Scale. RESULTS: Five patients were identified with eyelid movement disorders secondary to STN-DBS. All patients had moderate-to-severe symptoms at presentation. Four patients received periocular botulinum toxin injections. Three patients underwent surgery in the form of frontalis suspension or direct brow lift with or without upper lid blepharoplasty. All reported an improvement in symptoms following treatment. CONCLUSIONS: A multimodality, patient-specific approach is required in the treatment of blepharospasm/ALO secondary to STN-DBS. Botulinum toxin injections can be effective, but patients may require surgery if toxin treatment alone becomes ineffective. Tailoring treatment to individual needs can result in a measurable improvement in symptoms.

Circulating Citrate Is Associated with Liver Fibrosis in Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is associated with mitochondrial damage. Circulating mitochondrial metabolites may be elevated in NAFLD but their associations with liver damage is not known. This study aimed to assess the association of key mitochondrial metabolites with the degree of liver fibrosis in the context of NAFLD and nonalcoholic steatohepatitis (NASH). Cross-sectional analyses were performed on two cohorts of biopsy-proven NAFLD and/or NASH subjects. The association of circulating mitochondrial metabolite concentrations with liver fibrosis was assessed using linear regression analysis. In the single-center cohort of NAFLD subjects (n = 187), the mean age was 54.9 ±13.0 years, 40.1% were female and 86.1% were White. Type 2 diabetes (51.3%), hypertension (43.9%) and obesity (72.2%) were prevalent. Those with high citrate had a higher proportion of moderate/significant liver fibrosis (stage F ≥ 2) (68.4 vs. 39.6%, p = 0.001) and advanced fibrosis (stage F ≥ 3) (31.6 vs. 13.6%, p = 0.01). Citrate was associated with liver fibrosis independent of age, sex, NAFLD activity score and metabolic syndrome (per 1 SD increase: ß = 0.19, 95% CI: 0.03-0.35, p = 0.02). This association was also observed in a cohort of NASH subjects (n = 176) (ß = 0.21, 95% CI: 0.07-0.36, p = 0.005). The association of citrate with liver fibrosis was observed in males (p = 0.005) but not females (p = 0.41). In conclusion, circulating citrate is elevated and associated with liver fibrosis, particularly in male subjects with NAFLD and NASH. Mitochondrial function may be a target to consider for reducing the progression of liver fibrosis and NASH.

ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD.

BACKGROUND & AIMS: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and guide treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD. METHODS: We used aptamer-based proteomics to measure 4,783 proteins in 2 cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modeling-logistic regression assessed the ability of candidate proteins to classify fibrosis. RESULTS: From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n = 62) and B (n = 98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n = 71) and D (n = 84). The A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) protein accurately distinguished non-alcoholic fatty liver (NAFL)/non-alcoholic steatohepatitis (NASH) with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4, with AUROCs of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3), with AUROCs of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROCs 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROCs 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and fibrosis-4 score. CONCLUSION: The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis; they exhibited superior diagnostic performance compared to standard of care fibrosis scores. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in the blood which may identify fibrosis without the need for a liver biopsy.

Fibrosis-4 Index Can Independently Predict Major Adverse Cardiovascular Events in Nonalcoholic Fatty Liver Disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is closely associated with an increased risk of cardiovascular disease. We aimed to determine whether the fibrosis-4 index (FIB-4) can identify patients with NAFLD at highest risk of cardiovascular events. METHODS: We analyzed data from 81,108 patients with (i) a diagnosis of NAFLD, (ii) nonalcoholic steatohepatitis (NASH), or (iii) at risk (RISK) of NASH. The outcome of interest was major adverse cardiovascular events (MACE) defined by myocardial infarction, hospitalization for unstable angina or heart failure, and coronary revascularization. RESULTS: The mean age was 62 years, and 49.6% were men. Among 67,273 patients without previous cardiovascular disease, 9,112 (13.5%) experienced MACE over median follow-up of 3 years. In univariate analysis, a FIB-4 ≥2.67 was a significant predictor of MACE overall (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.63-2.04, P < 0.001) and across all baseline groups. After adjusting for established cardiovascular risk factors, FIB-4 ≥2.67 remained the strongest predictor of MACE overall (adjusted HR [aHR] 1.80, 95% CI 1.61-2.02, P < 0.001) and was consistently associated with myocardial infarction (aHR 1.46, 95% CI 1.25-1.70, P < 0.001), hospitalization for unstable angina (aHR 1.24, 95% CI 1.03-1.49, P = 0.025), hospitalization for heart failure (aHR 2.09, 95% CI 1.86-2.35, P < 0.001), coronary artery bypass graft (aHR 1.65, 95% CI 1.26-2.17, P < 0.001), and percutaneous coronary intervention (aHR 1.72, 95% CI 1.21-2.45, P = 0.003). DISCUSSION: In a large, real-world cohort of patients with NAFLD, NASH, or at RISK of NASH, the FIB-4 score was the strongest independent predictor of MACE, beyond established cardiovascular risk factors and baseline liver diagnosis.

Portrait of Regional Trends in Liver Transplantation for Nonalcoholic Steatohepatitis in the United States.

INTRODUCTION: Nonalcoholic steatohepatitis (NASH) is one of the most common etiologies of liver transplantation (LT) in the United States. We investigated regional trends in waitlist candidates, LT rates, and recipient survival among patients with NASH. METHODS: Using the United Network for Organ Sharing database by Organ Procurement and Transplantation Network regions, we investigated waitlist registration, LT rates, and survival for NASH between January 2004 and December 2019. RESULTS: The absolute number and percentage of total LT performed for NASH increased substantially in all Organ Procurement and Transplantation Network regions. In 2019, region 11 had the highest percentage of NASH-related LT with 31.4% followed by region 10 (25.3%) and region 8 (23.1%). Between 2015 and 2019, region 5 had the highest rising percentage in LT for NASH at 208%, followed by region 1 (194%) and region 4 (183%). The proportion of NASH hepatocellular carcinoma (NASH-HCC) was the highest in region 9 at 37.7% and lowest in region 10 (19.2%), region 3 (20.6%), and region 11 (20.8%). In multivariate analysis, diabetes (HR 1.18, P < 0.001), dialysis before LT (hazard ratio [HR] 1.53, P < 0.001), HCC (HR 1.19, P < 0.00), portal vein thrombosis (HR 1.24, P < 0.001), donor age (HR 1.026, P = 0.03), and recipient age (HR 1.24, P = <0.001) were associated with worse survival. DISCUSSION: LT for patients with NASH has dramatically increased across all regions since 2004, but with substantial heterogeneity among regions in the proportion with HCC and post-LT survival. Identifying contributing factors to these regional differences is warranted.

Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial.

BACKGROUND AND AIMS: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH. APPROACH AND RESULTS: A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least-squares mean percent change from baseline in ALT at week 16 was -25.5% (5.8), -27.7% (5.9), and -45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 µg/mL [0.3] vs. 1.3 µg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27). CONCLUSIONS: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).

Development and Psychometric Testing of a Knowledge Instrument on Incontinence-Associated Dermatitis for Clinicians: The Know-IAD.

PURPOSE: The purpose of this study was to describe the development and evaluation of the psychometric properties of an instrument used to assess clinician knowledge of Incontinence-associated dermatitis (IAD). DESIGN: The instrument was developed in three phases: Phase 1 involved item development; Phase 2 evaluated content validity of the instrument by surveying clinicians and stakeholders within a single state of Australia and, Phase 3 used a pilot multisite cross-sectional survey design to determine composite reliability and evaluate scores of the knowledge tool. SUBJECTS AND SETTINGS: In Phase 1, the instrument was developed by five persons with clinical and research subject expertise in the area of IAD. In Phase 2, content validity was evaluated by a group of 13 clinicians (nurses, physicians, occupational therapists, dietitians, and physiotherapists) working in acute care across one Australian state, New South Wales, along with two consumer representatives. In Phase 3, clinicians, working across six hospitals in New South Wales and on wards with patients diagnosed with incontinence-associated dermatitis, participated in pilot-testing the instrument. METHODS: During Phase 1, a group of local and international experts developed items for a draft tool based on an international consensus document, our prior research evaluating incontinence-associated dermatitis knowledge, and agreement among an expert panel of clinicians and researchers. Phase 2 used a survey design to determine content validity of the knowledge tool. Specifically, we calculated item- and scale-level content validity ratios and content validity indices for all questions within the draft instrument. Phase 3 comprised pilot-testing of the knowledge tool using a cross-sectional survey. Analysis involved confirmatory factor analysis to confirm the hypothesized model structure of the knowledge tool, as measured by model goodness-of-fit. Composite reliability testing was undertaken to determine the extent of internal consistency between constituent items of each construct. RESULTS: During Phase 1, a draft version of the Barakat-Johnson Incontinence-Associated Dermatitis Knowledge tool (Know-IAD), comprising 19 items and divided into three domains of IAD-related knowledge: 1) Etiology and Risk, 2) Classification and Diagnosis, and 3) Prevention and Management was developed. In Phase 2, 18 of the 19 items demonstrated high scale content validity ratios scores on relevance (0.75) and clarity (0.82); and high scale-content validity indices scores on relevance (0.87) and clarity (0.91). In Phase 3, the final 18-item Know-IAD tool demonstrated construct validity by a model goodness-of-fit. Construct validity was excellent for the Etiology and Risk domain (root mean squared error=0.02) and Prevention and Management domain (root mean squared error=0.02); it was good for the Classification and Diagnosis domain (root mean squared error=0.04). Composite reliability (CR) was good in the Etiology and Risk domain (CR=0.76), Prevention and Management domains (CR=0.75), and adequate in the Classification and Diagnosis domain (CR=0.64). Respondents had good understanding of etiology and risk (72.6% correct responses); fairly good understanding of prevention and management of IAD (64.0% correct responses) and moderate understanding of classification and diagnosis (40.2% correct responses). CONCLUSIONS: The Know-IAD demonstrated good psychometric properties and provides preliminary evidence that it can be applied to evaluate clinician knowledge on IAD.

Clinician Knowledge of Incontinence-Associated Dermatitis: A Multisite Survey of Healthcare Professionals in Acute and Subacute Settings.

PURPOSE: This study examined clinicians' knowledge of incontinence-associated dermatitis (IAD) using the Barakat-Johnson Incontinence-Associated Dermatitis Knowledge Tool (Know-IAD). DESIGN: A cross-sectional multicenter survey. SUBJECTS AND SETTING: The setting was 6 hospitals across 5 health districts in New South Wales, Australia. The participants were nurses (registered nurses and enrolled nurses), physicians, allied health (occupational therapists, dietitians, and physiotherapists), and students (nursing and allied health). METHODS: Data about IAD knowledge were collected from November 2019 to January 2020. The Know-IAD, an 18-item validated instrument that measures knowledge of IAD in 3 domains (etiology and risk, classification and diagnosis, and prevention and management), was administered to a cross section of eligible clinicians. The participants anonymously completed hard copy surveys. Descriptive and exploratory analyses were conducted to quantify clinicians' knowledge about the etiology and risk, classification and diagnosis, and prevention and management of IAD. A mean knowledge score of 70% was considered to be satisfactory. RESULTS: Four hundred twelve respondents completed the survey. One hundred twenty nine respondents (31.3%) achieved 70% correct responses and greater for the entire set of items. For the etiology and risk domain, 348 respondents (84.5%) obtained a score of 70% correct responses and greater, 67 respondents (16.3%) achieved 70% correct responses and greater for the classification and diagnosis domain, and 84 respondents (20.4%) achieved 70% correct responses and greater for the prevention and management domain. CONCLUSION: Clinicians tend to have low knowledge and recognition of IAD, particularly in the areas of classification and diagnosis along with prevention and management. They tend to have higher knowledge of how IAD is caused and the risk factors. This study has identified knowledge gaps for further education that can improve assessment, prevention, and management of IAD.

"There's a lot of talent in the room but it's only really the medical talent that gets heard": a qualitative exploration of multidisciplinary clinicians' perspectives of optimal nutrition care of patients with head and neck cancer.

BACKGROUND: The high prevalence of malnutrition in patients with head and neck cancer (HNC) negatively impacts outcomes. The best-available evidence has been published in clinical nutrition guidelines; however, translation into practice has lagged. AIM: This project aimed to explore multidisciplinary team (MDT) clinicians' perspectives regarding barriers and enablers to best-practice nutrition care in order to inform the design of a new model of care. METHOD: Qualitative interviews were conducted with clinicians who were purposively sampled from a major HNC tertiary referral centre in Sydney, Australia. To elicit information regarding barriers and facilitators to change, a semi-structured interview schedule was developed, interviews were transcribed verbatim and analyzed employing an inductive thematic approach. The Consolidated Framework for Implementation Research (CFIR) was used to guide data analysis and interpretation of key themes identified. RESULTS: Nineteen participants (11 supportive care and eight medical clinicians) representing allied health, medical, and nursing disciplines participated. Five key themes were identified: (1) acknowledgement of dietetics expertise and access to resources to deliver nutrition care; (2) proactive versus reactive nutrition care; (3) integrated and coordinated care-"The One Stop Shop"; (4) MDT favours the medical model; and (5) leadership-within disciplines, within the MDT. CONCLUSIONS: MDT clinicians expressed similar views regarding delivering optimal nutrition care to this high nutritional risk patient group. However, perspectives differed at times between medical and supportive care clinicians, attributable to perceptions that current service structure favours the medical model. In order to design and deliver an evidence-based model of care, specific strategies will be required to ensure: early and ongoing access to expert nutrition care; nutrition care processes are proactive; integrated and coordinated care; and leadership, both intra- and inter-disciplinary. This novel exploration of MDT clinicians' views provides supporting evidence that multi-component implementation strategies comprising individual, team and system-level approaches will be essential to leverage sustainable change.

Development of an Algorithm to Identify Cases of Nonalcoholic Steatohepatitis Cirrhosis in the Electronic Health Record.

BACKGROUND AND AIMS: Current genetic research of nonalcoholic steatohepatitis (NASH) cirrhosis is limited by our ability to accurately identify cases on a large scale. Our objective was to develop and validate an electronic health record (EHR) algorithm to accurately identify cases of NASH cirrhosis in the EHR. METHODS: We used Clinical Query 2, a search tool at Beth Israel Deaconess Medical Center, to create a pool of potential NASH cirrhosis cases (n = 5415). We created a training set of 300 randomly selected patients for chart review to confirm cases of NASH cirrhosis. Test characteristics of different algorithms, consisting of diagnosis codes, laboratory values, anthropomorphic measurements, and medication records, were calculated. The algorithms with the highest positive predictive value (PPV) and the highest F score with a PPV ≥ 80% were selected for internal validation using a separate random set of 100 patients from the potential NASH cirrhosis pool. These were then externally validated in another random set of 100 individuals using the research patient data registry tool at Massachusetts General Hospital. RESULTS: The algorithm with the highest PPV of 100% on internal validation and 92% on external validation consisted of ≥ 3 counts of "cirrhosis, no mention of alcohol" (571.5, K74.6) and ≥ 3 counts of "nonalcoholic fatty liver" (571.8-571.9, K75.81, K76.0) codes in the absence of any diagnosis codes for other common causes of chronic liver disease. CONCLUSIONS: We developed and validated an EHR algorithm using diagnosis codes that accurately identifies patients with NASH cirrhosis.

The presence of diabetes impacts liver fibrosis and steatosis by transient elastography in a primary care population.

INTRODUCTION AND OBJECTIVES: Noninvasive liver assessment in type 2 diabetes (T2DM) in a primary care population identifies higher risk non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate the association of T2DM with liver fibrosis and steatosis by transient elastography (TE). MATERIALS AND METHODS: This is a retrospective study of a TE referral program where primary care physicians were able to order TE. Patients with alcohol abuse were excluded. TE and Controlled Attenuation Parameter (CAP) scores were obtained. Multivariable linear and logistic regression models were used to adjust for confounders. RESULTS: 28% had T2DM. The mean TE score in T2DM patients was 8.3 (±6) kilopascal (kPa) and 6.4 (±3.7) kPa in those without T2DM (p = 0.0001). Those with T2DM had a higher CAP (322 ± 51 dB/m vs. 296 ± 57 dB/m, p < 0.0001). In multivariable analysis, T2DM was associated with TE score (ß: 1.9, 95% confidence interval [CI]: 0.74-3.1, p = 0.001) and CAP (ß: 2.8, 95% CI: 9.3-36.2, p = 0.001). Patients with T2DM had higher-risk TE scores and more steatosis by CAP. CONCLUSION: T2DM is associated with liver fibrosis and steatosis by TE within a primary care population. A TE referral pathway may be utilized for T2DM patients who are at higher risk of NAFLD and its complications.

Implementing best available evidence into practice for incontinence-associated dermatitis in Australia: A multisite multimethod study protocol.

AIMS: Incontinence-associated dermatitis (IAD) is an insidious and under-reported hospital-acquired complication which substantially impacts on patients' quality of life. A published international guideline and the Ghent Global IAD Categorisation Tool (GLOBIAD) outline the best available evidence for the optimal management of IAD. This study aims to implement theguideline and the GLOBIAD tool and evaluate the effect on IAD occurrences and sacral pressure injuries as well as patient, clinician and cost-effectiveness outcomes. MATERIALS AND METHODS: The study will employ a multi-method design across six hospitals in five health districts in Australia, and will be conducted in three phases (pre-implementation, implementation and post-implementation) over 19 months. Data collection will involve IAD and pressure injury prevalence audits for patient hospital admissions, focus groups with, and surveys of, clinicians, patient interviews, and collection of the cost of IAD hospital care and patient-related outcomes including quality of life. Eligible participants will be hospitalised adults over 18 years of age experiencing incontinence, and clinicians working in the study wards will be invited to participate in focus groups and surveys. CONCLUSION: The implementation of health district-wide evidence-based practices for IAD using a translational research approach that engages key stakeholders will allow the standardisation of IAD care that can potentially be applicable to a range of settings. Knowledge gained will inform future practice change in patient care and health service delivery and improve the quality of care for patients with IAD. Support at the hospital, state and national levels, coupled with a refined stakeholder-inclusive strategy, will enhance this project's success, sustainability and scalability beyond this existing project.

High Dietary Intake of Vegetable or Polyunsaturated Fats Is Associated With Reduced Risk of Hepatocellular Carcinoma.

BACKGROUND & AIMS: We investigated associations of intake of total fats, specific dietary fats, and fats from different food sources with risk of hepatocellular carcinoma (HCC) using data from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). METHODS: We analyzed data from a total of 138,483 women and men who participated in the NHS or HPFS. A validated semi-quantitative food frequency questionnaire was sent to NHS participants in 1980, 1984, 1986, and every 4 years thereafter; dietary information was collected from participants in the HPFS in 1986 and every 4 years thereafter. Multivariable hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression. RESULTS: After an average follow-up time of 26.6 years, 160 incident HCC cases were documented. Although there was a non-significant association between total fat intake and HCC, intake of vegetable fats reduced risk of HCC (HR for the highest vs lowest quartile, 0.61; 95% CI, 0.39-0.96; Ptrend = .02), but not animal or dairy fats. Replacing animal or dairy fats with an equivalent amount of vegetable fats was associated with a lower risk of HCC (HR per 1 standard deviation, 0.79; 95% CI, 0.65-0.97). Among fat subtypes, monounsaturated and polyunsaturated fatty acids, including n-3 (HR, 0.63; 95% CI, 0.41-0.96; Ptrend = .14) and n-6 polyunsaturated fatty acids (HR, 0.54; 95% CI, 0.34-0.86; Ptrend = .02), were inversely associated with risk of HCC. Higher ratios of monounsaturated or polyunsaturated fat to saturated fat were inversely associated with HCC risk (all Ptrend ≤ .02). In addition, when replacing saturated fats with monounsaturated or polyunsaturated fats, the HR per 1 standard deviation was 0.77 (95% CI, 0.64-0.92). CONCLUSIONS: In an analysis of data from 2 large cohort studies, we found higher intake of vegetable fats and polyunsaturated fats to be associated with lower risk of HCC. Replacing animal or dairy fats with vegetable fats, or replacing saturated fats with monounsaturated or polyunsaturated fats, was associated with reduced risk of HCC.