Association of Baseline Hepatitis B Virus DNA and On-Treatment Risk of Cirrhosis and Hepatocellular Carcinoma.

Background: Recent studies suggest an inverse relationship between baseline levels of hepatitis B virus (HBV) DNA and on-treatment risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, data are limited to Asian cohorts, and it is unclear if similar associations hold true for non-Asians with CHB. We aimed to evaluate association of baseline HBV DNA with long-term risks of cirrhosis and HCC among a predominantly non-Asian cohort of CHB patients in the USA. Methods: Using longitudinal data from the national Veterans Affairs database, we evaluated the risk of cirrhosis or HCC among adults with non-cirrhotic CHB who are on continuous antiviral therapy, stratified by moderate levels of baseline HBV DNA (4.00 - 6.99 log10 IU/mL) vs. high levels of baseline HBV DNA (7.00 log10 IU/mL or higher). Propensity score weighting was applied, and competing risks cumulative incidence functions and Cox proportional hazards models were utilized. Results: Among 1,129 non-cirrhotic CHB patients (41% non-Hispanic White, 36% African American, mean age 57.0 years, 62.2% hepatitis B e antigen (HBeAg) positive), 585 had moderate levels of baseline HBV DNA and 544 had high HBV DNA. After propensity score weighting, no significant difference in risk of cirrhosis was observed between moderate vs. high baseline HBV DNA (4.55 vs. 5.22 per 100 person-years, hazard ratio (HR): 0.87, 95% confidence interval (CI): 0.69 - 1.09, P = 0.22), but risk of HCC was significantly higher in patients with moderate vs. high baseline HBV DNA (0.84 vs. 0.69 per 100 person-years, HR: 1.33, 95% CI: 1.09 - 1.62, P < 0.01). Conclusions: Among a national cohort of predominantly non-Asian US veterans with non-cirrhotic CHB on antiviral therapy, moderate levels of baseline HBV DNA was associated with higher risk of HCC than high HBV DNA.

Higher adiposity predicts greater intra-individual inconsistencies in postprandial glycemic measurements-an analysis of three randomized controlled trials in Asian populations.

BACKGROUND/OBJECTIVES: Acute glycemic responses offer important insights into glucose homeostasis although the repeatability of these measurements particularly in Asian populations remains unclear. This research aimed to critically investigate the inconsistencies of the postprandial glycemic profile within individuals, and identify potential variables predicting greater inconsistencies. SUBJECTS/METHODS: This was a secondary analysis of three randomized controlled trials which fed subjects with glucose (and other carbohydrate-rich foods), and measured postprandial blood glucose at regular intervals. Intra-individual rank-order consistency in the glycemic profile between acute glucose treatments was evaluated and compared against demographic, anthropometric and cardio-metabolic health related indicators to delineate potential confounding variables. Correlations between the incremental area under curve at 120 min (iAUC120 min) for glucose and the carbohydrate-rich foods were further explored. RESULTS: Rank-order consistency was identified to be moderate, with intra-individual inconsistencies marginally lower than inter-individual inconsistencies. Notably, greater inconsistencies within individuals were directly correlated with BMI and fat-mass index (P < 0.01) albeit non-significant for age, ethnicity, and other cardio-metabolic health-related risk indicators. Across the trials, there were positive monotonic correlations between the iAUC120 min for glucose and simple sugars (sucrose, isomaltulose), as well as different varieties of rice (jasmine white, Bapatla brown, Bapatla white; p < 0.05). However, there were a lack of associations between iAUC120 min for glucose with pastas (semolina and wholegrain penne, spaghetti) and mee pok noodles. CONCLUSION: There are inherent inconsistencies in postprandial glycemic measurements within individuals, particularly among those with higher adiposity. These confounders need to be kept in mind for appropriate and meaningful interpretations of glycemia.

Identification of hepatic steatosis among persons with and without HIV using natural language processing.

BACKGROUND: Steatotic liver disease (SLD) is a growing phenomenon, and our understanding of its determinants has been limited by our ability to identify it clinically. Natural language processing (NLP) can potentially identify hepatic steatosis systematically within large clinical repositories of imaging reports. We validated the performance of an NLP algorithm for the identification of SLD in clinical imaging reports and applied this tool to a large population of people with and without HIV. METHODS: Patients were included in the analysis if they enrolled in the Veterans Aging Cohort Study between 2001 and 2017, had an imaging report inclusive of the liver, and had ≥2 years of observation before the imaging study. SLD was considered present when reports contained the terms "fatty," "steatosis," "steatotic," or "steatohepatitis." The performance of the SLD NLP algorithm was compared to a clinical review of 800 reports. We then applied the NLP algorithm to the first eligible imaging study and compared patient characteristics by SLD and HIV status. RESULTS: NLP achieved 100% sensitivity and 88.5% positive predictive value for the identification of SLD. When applied to 26,706 eligible Veterans Aging Cohort Study patient imaging reports, SLD was identified in 72.2% and did not significantly differ by HIV status. SLD was associated with a higher prevalence of metabolic comorbidities, alcohol use disorder, and hepatitis B and C, but not HIV infection. CONCLUSIONS: While limited to those undergoing radiologic study, the NLP algorithm accurately identified SLD in people with and without HIV and offers a valuable tool to evaluate the determinants and consequences of hepatic steatosis.

Severe Acute Liver Injury After Hepatotoxic Medication Initiation in Real-World Data.

Importance: Current approaches to classify the hepatotoxic potential of medications are based on cumulative case reports of acute liver injury (ALI), which do not consider the size of the exposed population. There is little evidence from real-world data (data relating to patient health status and/or the delivery of health care routinely collected from sources outside of a research setting) on incidence rates of severe ALI after initiation of medications, accounting for duration of exposure. Objective: To identify the most potentially hepatotoxic medications based on real-world incidence rates of severe ALI and to examine how these rates compare with categorization based on case reports. Design, Setting, and Participants: This series of cohort studies obtained data from the US Department of Veterans Affairs on persons without preexisting liver or biliary disease who initiated a suspected hepatotoxic medication in the outpatient setting between October 1, 2000, and September 30, 2021. Data were analyzed from June 2020 to November 2023. Exposures: Outpatient initiation of any one of 194 medications with 4 or more published reports of hepatotoxicity. Main Outcomes and Measures: Hospitalization for severe ALI, defined by either inpatient: (1) alanine aminotransferase level greater than 120 U/L plus total bilirubin level greater than 2.0 mg/dL or (2) international normalized ratio of 1.5 or higher plus total bilirubin level greater than 2.0 mg/dL recorded within the first 2 days of admission. Acute or chronic liver or biliary disease diagnosis recorded during follow-up or as a discharge diagnosis of a hospitalization for severe ALI resulted in censoring. This study calculated age- and sex-adjusted incidence rates of severe ALI and compared observed rates with hepatotoxicity categories based on cumulative published case reports. Results: The study included 7 899 888 patients across 194 medication cohorts (mean [SD] age, 64.4 [16.4] years, 7 305 558 males [92.5%], 4 354 136 individuals [55.1%] had polypharmacy). Incidence rates of severe ALI ranged from 0 events per 10 000 person-years (candesartan, minocycline) to 86.4 events per 10 000 person-years (stavudine). Seven medications (stavudine, erlotinib, lenalidomide or thalidomide, chlorpromazine, metronidazole, prochlorperazine, and isoniazid) exhibited rates of 10.0 or more events per 10 000 person-years, and 10 (moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin) had rates between 5.0 and 9.9 events per 10 000 person-years. Of these 17 medications with the highest observed rates of severe ALI, 11 (64%) were not included in the highest hepatotoxicity category when based on case reports. Conclusions and Relevance: In this study, incidence rates of severe ALI using real-world data identified the most potentially hepatotoxic medications and can serve as a tool to investigate hepatotoxicity safety signals obtained from case reports. Case report counts did not accurately reflect the observed rates of severe ALI after medication initiation.

Incipient Intracholecystic Papillary Neoplasm of the Gallbladder Without Dysplasia.

Intracholecystic papillary neoplasm (ICPN) of the gallbladder is a rare tumor described as a mucosal exophytic neoplastic lesion that projects into the gallbladder lumen. In regards to the size, lesions that did not make the arbitrary 1cm cutoff are described as "incipient" ICPN. Not much is known about these incipient ICPNs, as they are often excluded in ICPN studies, given the attempted adherence to the traditional 1cm cutoff. We present the youngest reported case of incipient, non-mucinous gastric-pylorus type ICPN who underwent cholecystectomy. Resection with negative margin for ICPN appears to be sufficient treatment and post resection imaging surveillance could be of value but further studies are required.

Appropriateness of Antibiotic Prescribing in US Emergency Department Visits, 2016-2021.

In this national analysis of US emergency department visits with antibiotic prescribing during 2016-2021, 27.6% of visits resulted in inappropriate antibiotic prescribing: 14.9% had diagnosis codes plausibly antibiotic-related (eg, acute bronchitis), suggesting actual inappropriate prescribing, and 12.6% had diagnosis codes not plausibly antibiotic-related (eg, hypertension), suggesting poor coding quality.

Prevalence of Inappropriate Antibiotic Prescribing with or without a Plausible Antibiotic Indication among Safety-Net and Non-Safety Net Populations.

BACKGROUND: Clinicians can prescribe antibiotics inappropriately without coding the indication for antibiotics. Whether the prevalence of inappropriate antibiotic prescribing with or without a plausible indication differs between safety-net and non-safety-net populations is unknown. OBJECTIVE: To assess differences in inappropriate antibiotic prescribing with or without a plausible indication between safety-net and non-safety net populations. DESIGN: Cross-sectional. PARTICIPANTS: Office visits in the 2016, 2018, 2019 National Ambulatory Medical Care Survey with ≥ 1 antibiotic prescription among children (0-17 years) and adults (18-64 years). MAIN MEASURES: Inappropriate antibiotic prescribing with a plausible indication (visits with infection-related diagnosis codes that do not warrant antibiotics, e.g., acute bronchitis); inappropriate prescribing without a plausible indication (visits with codes that are not antibiotic indications, e.g., hypertension). By age group, we used linear regression to assess differences between safety-net (public/no insurance) and non-safety net populations (privately insured), controlling for patient and visit characteristics. KEY RESULTS: Analyses included 67,065,108 and 122,731,809 weighted visits for children and adults, respectively. Among visits for children in the safety-net and non-safety populations, the prevalence of inappropriate antibiotic prescribing with a plausible indication was 11.7% and 22.0% (adjusted difference: -8.0%, 95% CI: -17.1%, 1.0%); the prevalence of inappropriate prescribing without a plausible indication was 11.8% and 8.6% (adjusted difference: -2.0%, 95% CI: -4.6%, 0.6%). Among visits for adults in the safety-net and non-safety populations, the prevalence of inappropriate antibiotic prescribing with a plausible indication was 12.1% and 14.3% (adjusted difference: -0.1%, 95% CI -9.4%, 9.1%); the prevalence of inappropriate prescribing without a plausible indication was 48.2% and 32.3% (adjusted difference: 12.5%, 95% CI: 3.6%, 21.4%). CONCLUSIONS: Inappropriate antibiotic prescribing with or without a plausible antibiotic indication is common in all populations, highlighting the importance of broad-based antibiotic stewardship initiatives. However, targeted initiatives focused on improving coding quality in adult safety-net settings may be warranted.

Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B: A comprehensive review of phases II and III therapeutic agents.

Chronic hepatitis B virus (HBV) infection affects over 295 million people globally and an estimated 1.6 million people in the United States. It is associated with significant morbidity and mortality due to cirrhosis, liver failure, and liver cancer. Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression, which in turn has been associated with a decreased risk of liver complications. However, current antiviral regimens are limited by concerns with adverse effects, adherence, resistance, long-term treatment, and ongoing risk for liver events. Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen (HBsAg) loss and suppression of HBV DNA. Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B, including core/capsid inhibitors, entry inhibitors, RNA interference (siRNA/ASO), HBsAg inhibitors, Toll-like receptor agonists, checkpoint inhibitors, and therapeutic vaccines.

An explainable machine learning model for prediction of high-risk nonalcoholic steatohepatitis.

Early identification of high-risk metabolic dysfunction-associated steatohepatitis (MASH) can offer patients access to novel therapeutic options and potentially decrease the risk of progression to cirrhosis. This study aimed to develop an explainable machine learning model for high-risk MASH prediction and compare its performance with well-established biomarkers. Data were derived from the National Health and Nutrition Examination Surveys (NHANES) 2017-March 2020, which included a total of 5281 adults with valid elastography measurements. We used a FAST score ≥ 0.35, calculated using liver stiffness measurement and controlled attenuation parameter values and aspartate aminotransferase levels, to identify individuals with high-risk MASH. We developed an ensemble-based machine learning XGBoost model to detect high-risk MASH and explored the model's interpretability using an explainable artificial intelligence SHAP method. The prevalence of high-risk MASH was 6.9%. Our XGBoost model achieved a high level of sensitivity (0.82), specificity (0.91), accuracy (0.90), and AUC (0.95) for identifying high-risk MASH. Our model demonstrated a superior ability to predict high-risk MASH vs. FIB-4, APRI, BARD, and MASLD fibrosis scores (AUC of 0.95 vs. 0.50, 0.50, 0.49 and 0.50, respectively). To explain the high performance of our model, we found that the top 5 predictors of high-risk MASH were ALT, GGT, platelet count, waist circumference, and age. We used an explainable ML approach to develop a clinically applicable model that outperforms commonly used clinical risk indices and could increase the identification of high-risk MASH patients in resource-limited settings.

Most Orthopaedic Platelet-Rich Plasma Investigations Don't Report Protocols and Composition: An Updated Systematic Review.

PURPOSE: To systematically review the literature to assess the heterogeneity of platelet-rich plasma (PRP) preparation and composition reporting for the treatment of musculoskeletal/orthopaedic pathologies. METHODS: A systematic review was performed by searching PubMed, the Cochrane Library, and Embase to identify Level I and Level II studies from 2016 to 2022 that evaluated the use of PRP therapy for musculoskeletal pathologies. The search phrase used was "platelet-rich plasma clinical studies." Studies were assessed based on their reporting of the PRP preparation methods and reporting of PRP composition. RESULTS: One hundred twenty-four studies (in 120 articles) met inclusion criteria for analysis. Of these studies, 15 (12.1%) provided comprehensive reporting, including a clear, well-described, and reproducible preparation protocol that future investigators can follow. Thirty-three studies (26.6%) quantitatively reported the final PRP product composition. CONCLUSIONS: Among the studies using PRP for the treatment of musculoskeletal/orthopaedic pathologies, less than 20% provided a clear, well-described, and reproducible PRP preparation protocol, and only one-fourth of studies reported on the final PRP product composition. CLINICAL RELEVANCE: A diverse current reporting of PRP composition between studies provides a high heterogeneity of the term "PRP," which becomes a limitation for a comparison of studies using PRP.

Prevalence and characteristics of hepatitis delta virus infection in patients with hepatitis B in the United States: An analysis of the All-Payer Claims Database.

BACKGROUND AND AIMS: HDV leads to the most severe form of viral hepatitis; however, the prevalence of HDV is not well understood. Using real-world data from the All-Payer Claims Database, this study estimates the prevalence of HBV/HDV infection among the chronic HBV population and describes patient/clinical characteristics for adults with HBV/HDV infection in the United States. APPROACH AND RESULTS: Adults (≥18 years) with ≥1 inpatient claim or ≥2 outpatient claims for HDV infection or HBV in the All-Payer Claims Database from January 1, 2014, to December 31, 2020, were identified. HDV prevalence was calculated as the proportion of patients with HBV/HDV infection among total patients with HBV infection. Patient characteristics, socioeconomic status, advanced liver complications (eg, cirrhosis, HCC), and comorbidities were assessed. A total of 6719 patients were diagnosed with HBV/HDV among 144,975 with HBV and 12 months of continuous data, for a prevalence of 4.6%. At diagnosis, 31.7% of patients with HBV/HDV had advanced liver complications, including compensated cirrhosis (16.3%) and decompensated cirrhosis (10.4%). Diabetes (50.5%), hypertension (49.8%), and HIV infection (30.9%) were the top 3 comorbidities. CONCLUSIONS: In a large database capturing approximately 80% of the US-insured population, HBV/HDV infection prevalence was 4.6% among adults infected with HBV. Patients infected with HDV had high rates of baseline liver complications and other comorbidities at the time of diagnosis, suggesting potentially delayed diagnosis and/or treatment. Earlier identification of HBV/HDV infection among the population with HBV may provide opportunities to improve linkage to care and treatment, thereby reducing the risk of liver-related morbidity and mortality.

Attenuating Epithelial-to-Mesenchymal Transition in Cancer through Angiopoietin-Like 4 Inhibition in a 3D Tumor Microenvironment Model.

Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastatic cancer progression, and current research, which relies heavily on 2D monolayer cultures, falls short in recapitulating the complexity of a 3D tumor microenvironment. To address this limitation, a transcriptomic meta-analysis is conducted on diverse cancer types undergoing EMT in 2D and 3D cultures. It is found that mechanotransduction is elevated in 3D cultures and is further intensified during EMT, but not during 2D EMT. This analysis reveals a distinct 3D EMT gene signature, characterized by extracellular matrix remodeling coordinated by angiopoietin-like 4 (Angptl4) along with other canonical EMT regulators. Utilizing hydrogel-based 3D matrices with adjustable mechanical forces, 3D cancer cultures are established at varying physiological stiffness levels. A YAP:EGR-1 mediated up-regulation of Angptl4 expression is observed, accompanied by an upregulation of mesenchymal markers, at higher stiffness during cancer EMT. Suppression of Angptl4 using antisense oligonucleotides or anti-cAngptl4 antibodies leads to a dose-dependent abolishment of EMT-mediated chemoresistance and tumor self-organization in 3D, ultimately resulting in diminished metastatic potential and stunted growth of tumor xenografts. This unique programmable 3D cancer cultures simulate stiffness levels in the tumor microenvironment and unveil Angptl4 as a promising therapeutic target to inhibit EMT and impede cancer progression.