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BACKGROUND AND AIMS: Ensemble machine-learning methods, like the superlearner, combine multiple models into a single one to enhance predictive accuracy. Here we explore the potential of the superlearner as a benchmarking tool for clinical risk prediction, illustrating the approach to identifying significant liver fibrosis among patients with NAFLD. APPROACH AND RESULTS: We used 23 demographic/clinical variables to train superlearner(s) on data from the NASH-clinical research network observational study (n = 648) and validated models with data from the FLINT trial (n = 270) and National Health and Nutrition Examination Survey (NHANES) participants with NAFLD (n = 1244). Comparing the superlearner's performance to existing models (Fibrosis-4 [FIB-4], NAFLD fibrosis score, Forns, AST to Platelet Ratio Index [APRI], BARD, and Steatosis-Associated Fibrosis Estimator [SAFE]), it exhibited strong discriminative ability in the FLINT and NHANES validation sets, with AUCs of 0.79 (95% CI: 0.73-0.84) and 0.74 (95% CI: 0.68-0.79) respectively. CONCLUSIONS: Notably, the SAFE score performed similarly to the superlearner, both of which outperformed FIB-4, APRI, Forns, and BARD scores in the validation data sets. Surprisingly, the superlearner derived from 12 base models matched the performance of one with 90 base models. Overall, the superlearner, being the "best-in-class" machine-learning predictor, excelled in detecting fibrotic NASH, and this approach can be used to benchmark the performance of conventional clinical risk prediction models.
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BACKGROUND AND AIMS: A single-nation study reported that pretreatment HBV viral load is associated with on-treatment risk of HCC in patients who are HBeAg-positive without cirrhosis and with chronic hepatitis B initiating antiviral treatment. We aimed to validate the association between baseline HBV viral load and on-treatment HCC risk in a larger, multinational cohort. APPROACH AND RESULTS: Using a multinational cohort from Korea, Hong Kong, and Taiwan involving 7545 adult patients with HBeAg-positive, without cirrhosis and with chronic hepatitis B who started entecavir or tenofovir treatment with baseline HBV viral load ≥5.00 log 10 IU/mL, HCC risk was estimated by baseline viral load. HBV viral load was analyzed as a categorical variable. During continuous antiviral treatment (median, 4.28 y), HCC developed in 200 patients (incidence rate, 0.61 per 100 person-years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a nonlinear pattern. HCC risk was lowest with the highest baseline viral load (≥8.00 log 10 IU/mL; incidence rate, 0.10 per 100 person-years), but increased sharply as baseline viral load decreased. The adjusted HCC risk was 8.05 times higher (95% CI, 3.34-19.35) with baseline viral load ≥6.00 and <7.00 log 10 IU/mL (incidence rate, 1.38 per 100 person-years) compared with high (≥8.00 log 10 IU/mL) baseline viral load ( p <0.001). CONCLUSIONS: In a multinational cohort of adult patients with HBeAg-positive without cirrhosis and with chronic hepatitis B, baseline HBV viral load was significantly associated with HCC risk despite antiviral treatment. Patients with the highest viral load who initiated treatment had the lowest long-term risk of HCC development.
Subject(s)
Antiviral Agents , Carcinoma, Hepatocellular , Hepatitis B e Antigens , Hepatitis B, Chronic , Liver Neoplasms , Viral Load , Humans , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/virology , Male , Liver Neoplasms/virology , Liver Neoplasms/epidemiology , Liver Neoplasms/etiology , Female , Middle Aged , Hepatitis B e Antigens/blood , Antiviral Agents/therapeutic use , Carcinoma, Hepatocellular/virology , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/etiology , Adult , Taiwan/epidemiology , Hepatitis B virus , Hong Kong/epidemiology , Republic of Korea/epidemiology , Cohort Studies , Tenofovir/therapeutic use , Guanine/analogs & derivatives , Guanine/therapeutic use , DNA, Viral/blood , Incidence , Risk FactorsABSTRACT
Acute-on-chronic liver failure (ACLF) is a variably defined syndrome characterized by acute decompensation of cirrhosis with organ failures. At least 13 different definitions and diagnostic criteria for ACLF have been proposed, and there is increasing recognition that patients with ACLF may face disadvantages in the current United States liver allocation system. There is a need, therefore, for more standardized data collection and consensus to improve study design and outcome assessment in ACLF. In this article, we discuss the current landscape of transplantation for patients with ACLF, strategies to optimize organ utility, and data opportunities based on emerging technologies to facilitate improved data collection.
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Medical literature highlights differences in liver transplantation (LT) waitlist experiences among ABO blood types. Type AB candidates reportedly have higher LT rates and reduced mortality. Despite liver offering guidelines, ABO disparities persist. This study examines LT access discrepancies among blood types, focusing on type AB, and seeks equitable strategies. Using the United Network for Organ Sharing database (2003-2022), 170 276 waitlist candidates were retrospectively analyzed. Dual predictive analyses (LT opportunity and survival studies) evaluated 1-year recipient pool survival, considering waitlist and post-LT survival, alongside anticipated allocation value per recipient, under 6 scenarios. Of the cohort, 97 670 patients (57.2%) underwent LT. Type AB recipients had the highest LT rate (73.7% vs 55.2% for O), shortest median waiting time (90 vs 198 days for A), and lowest waitlist mortality (12.9% vs 23.9% for O), with the lowest median model for end-stage liver disease-sodium (MELD-Na) score (20 vs 25 for A/O). The LT opportunity study revealed that reallocating type A (or A and O) donors originally for AB recipients to A recipients yielded the greatest reduction in disparities in anticipated value per recipient, from 0.19 (before modification) to 0.08. Meanwhile, the survival study showed that ABO-identical LTs reduced disparity the most (3.5% to 2.8%). Sensitivity analysis confirmed these findings were specific to the MELD-Na score < 30 population, indicating current LT allocation may favor certain blood types. Prioritizing ABO-identical LTs for MELD-Na score < 30 recipients could ensure uniform survival outcomes and mitigate disparities.
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In 2022, liver transplant activity continued to increase in the United States, with an all-time high of 9,527 transplants performed, representing a 52% increase over the past decade (2012-2022). Of these transplants, 8,924 (93.7%) were from deceased donors and 603 (6.3%) were from living donors. Liver transplant recipients were 94.5% adult and 5.5% pediatric. The overall size of the liver transplant waiting list contracted, with more patients being removed than added, although 10,548 adult patients still remained on the waiting list at the end of 2022. Alcohol-associated liver disease continued to be the leading diagnosis among both candidates and recipients, followed by metabolic dysfunction-associated steatohepatitis. Simultaneous liver-kidney transplant was the most common multiorgan combination, with 800 liver-kidney transplants performed in 2022; in addition, there were 303 new listings for kidney transplant via the safety net mechanism. Among adults added to the liver waiting list in 2021, 39.9% received a deceased donor liver transplant within 3 months; 45.7%, within 6 months; and 54.5%, within 1 year. Pretransplant mortality decreased to 12.3 deaths per 100 patient-years in 2022, although still 15.6% of removals from the waiting list were for death or being too sick for transplant. Graft and patient survival outcomes after deceased donor liver transplant improved, approximating pre-COVID-19 pandemic levels, with 5.1% mortality observed at 6 months; 6.8%, at 1 year; 12.7%, at 3 years; 19.8%, at 5 years; and 35.7%, at 10 years. Five-year graft and patient survival rates after living donor liver transplant exceeded those of deceased donor liver transplant. Candidates receiving model for end-stage liver disease exception points for hepatocellular carcinoma constituted 15.5% of transplants performed in 2022, with similar transplant rates and posttransplant outcomes compared to cases without hepatocellular carcinoma exception. In 2022, more pediatric liver transplant candidates were added to the waiting list and underwent transplant compared with either of the preceding 2 years, with an uptick in living donor liver transplant volume. Although pretransplant mortality has improved after the recent policy change prioritizing pediatric donors for pediatric recipients, still, in 2022, 50 children died or were removed from the waiting list for being too sick to undergo transplant. Posttransplant mortality among pediatric liver transplant recipients remained notable, with death occurring in 4.0% at 6 months, 6.0% at 1 year, 8.2% at 3 years, 9.8% at 5 years, and 13.9% at 10 years. Similar to adult living donor recipients, pediatric living donor recipients had better 5-year patient survival compared with deceased donor recipients.
Subject(s)
Carcinoma, Hepatocellular , End Stage Liver Disease , Liver Neoplasms , Liver Transplantation , Tissue and Organ Procurement , Adult , Humans , Child , United States/epidemiology , Living Donors , Pandemics , Severity of Illness Index , Tissue Donors , Waiting Lists , Graft SurvivalABSTRACT
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD),1 represents a global public health issue. Fibrosis stage is the most important risk for long-term undesirable outcomes.2,3 From recent meta-analyses, all-cause and liver-related mortalities significantly increased from fibrosis stage 2 (significant fibrosis; F≥2) onward.4,5 In primary care setting, those with F≥2 should be referred to hepatologists; therefore, noninvasive tests to stratify risk of patients with MASLD are crucial. Steatosis-associated fibrosis estimator (SAFE) was recently developed to predict F≥2.6 SAFE has been externally validated and outperformed fibrosis-4 (FIB-4) and NAFLD fibrosis score (NFS).7,8 Recently, international guidelines proposed sequential diagnostic steps, initially using FIB-4 and then transient elastography (TE) in non-low-risk patients.9,10 However, the guidelines focused on identifying advanced fibrosis (F≥3), which might be too late. This study aimed to compare the performance among SAFE, FIB-4, and NFS, and evaluate SAFE-TE sequential approach. We hypothesized that by initially using SAFE, the proportion of patients misclassified as low risk despite already having F≥2 could be diminished.
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BACKGROUND & AIMS: Continuous risk-stratification of candidates and urgency-based prioritization have been utilized for liver transplantation (LT) in patients with non-hepatocellular carcinoma (HCC) in the United States. Instead, for patients with HCC, a dichotomous criterion with exception points is still used. This study evaluated the utility of the hazard associated with LT for HCC (HALT-HCC), an oncological continuous risk score, to stratify waitlist dropout and post-LT outcomes. METHODS: A competing risk model was developed and validated using the UNOS database (2012-2021) through multiple policy changes. The primary outcome was to assess the discrimination ability of waitlist dropouts and LT outcomes. The study focused on the HALT-HCC score, compared with other HCC risk scores. RESULTS: Among 23,858 candidates, 14,646 (59.9%) underwent LT and 5196 (21.8%) dropped out of the waitlist. Higher HALT-HCC scores correlated with increased dropout incidence and lower predicted 5-year overall survival after LT. HALT-HCC demonstrated the highest area under the curve (AUC) values for predicting dropout at various intervals post-listing (0.68 at 6 months, 0.66 at 1 year), with excellent calibration (R2 = 0.95 at 6 months, 0.88 at 1 year). Its accuracy remained stable across policy periods and locoregional therapy applications. CONCLUSIONS: This study highlights the predictive capability of the continuous oncological risk score to forecast waitlist dropout and post-LT outcomes in patients with HCC, independent of policy changes. The study advocates integrating continuous scoring systems like HALT-HCC in liver allocation decisions, balancing urgency, organ utility, and survival benefit.
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The use of older donors after circulatory death (DCD) for liver transplantation (LT) has increased over the past decade. This study examined whether outcomes of LT using older DCD (≥50 y) have improved with advancements in surgical/perioperative care and normothermic machine perfusion (NMP) technology. A total of 7602 DCD LT cases from the United Network for Organ Sharing database (2003-2022) were reviewed. The impact of older DCD donors on graft survival was assessed using the Kaplan-Meier and HR analyses. In all, 1447 LT cases (19.0%) involved older DCD donors. Although there was a decrease in their use from 2003 to 2014, a resurgence was noted after 2015 and reached 21.9% of all LTs in the last 4 years (2019-2022). Initially, 90-day and 1-year graft survivals for older DCDs were worse than younger DCDs, but this difference decreased over time and there was no statistical difference after 2015. Similarly, HRs for graft loss in older DCD have recently become insignificant. In older DCD LT, NMP usage has increased recently, especially in cases with extended donor-recipient distances, while the median time from asystole to aortic cross-clamp has decreased. Multivariable Cox regression analyses revealed that in the early phase, asystole to cross-clamp time had the highest HR for graft loss in older DCD LT without NMP, while in the later phases, the cold ischemic time (>5.5 h) was a significant predictor. LT outcomes using older DCD donors have become comparable to those from young DCD donors, with recent HRs for graft loss becoming insignificant. The strategic approach in the recent period could mitigate risks, including managing cold ischemic time (≤5.5 h), reducing asystole to cross-clamp time, and adopting NMP for longer distances. Optimal use of older DCD donors may alleviate the donor shortage.
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As the global surfactant market continues to expand, there is an increasing need to develop bio-based alternatives in the shift towards a circular economy. This study focuses on the synthesis of polar, amphoteric, amine-oxide surfactants starting from biomass-derived monosaccharides and demonstrating their potential in various applications. The synthesis involved a reductive amination of the sugars with an alkylamine and formaldehyde followed by oxidation to produce N-oxide surfactants. These bio-based surfactants exhibited promising properties, including high solubility, foamability, surface tension reduction, and critical micelle concentration. In particular, N-GalA1.10 and N-GalA1.12 showed comparable performance to commercial surfactants. Furthermore, these bio-based surfactants demonstrated significantly lower skin irritation potential when compared to petrochemical-derived counterparts like sodium laureth sulfate (SLES), making them potentially suitable for personal care products. The biodegradability assessment revealed that N-GalA1.12 exhibited good biodegradation, indicating its potential environmental compatibility. In conclusion, this study highlights the potential of bio-based N-oxide surfactants derived from monosaccharides as sustainable and skin-friendly alternatives to traditional amphoteric surfactants, like cocamidopropyl betaine (CAPB).
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BACKGROUND: Introducing new liver transplantation (LT) practices, like unconventional donor use, incurs higher costs, making evaluation of their prognostic justification crucial. This study reexamines the spread pattern of new LT practices and its prognosis across the United States. METHODS: The study investigated the spread pattern of new practices using the UNOS database (2014-2023). Practices included LT for hepatitis B/C (HBV/HCV) nonviremic recipients with viremic donors, LT for COVID-19-positive recipients, and LT using onsite machine perfusion (OMP). One year post-LT patient and graft survival were also evaluated. RESULTS: LTs using HBV/HCV donors were common in the East, while LTs for COVID-19 recipients and those using OMP started predominantly in California, Arizona, Texas, and the Northeast. K-means cluster analysis identified three adoption groups: facilities with rapid, slow, and minimal adoption rates. Rapid adoption occurred mainly in high-volume centers, followed by a gradual increase in middle-volume centers, with little increase in low-volume centers. The current spread patterns did not significantly affect patient survival. Specifically, for LTs with HCV donors or COVID-19 recipients, patient and graft survivals in the rapid-increasing group was comparable to others. In LTs involving OMP, the rapid- or slow-increasing groups tended to have better patient survival (p = 0.05) and significantly improved graft survival rates (p = 0.02). Facilities adopting new practices often overlap across different practices. DISCUSSION: Our analysis revealed three distinct adoption groups across all practices, correlating the adoption aggressiveness with LT volume in centers. Aggressive adoption of new practices did not compromise patient and graft survivals, supporting the current strategy. Understanding historical trends could predict the rise in future LT cases with new practices, aiding in resource distribution.
Subject(s)
COVID-19 , Graft Survival , Liver Transplantation , SARS-CoV-2 , Humans , Liver Transplantation/statistics & numerical data , United States/epidemiology , COVID-19/epidemiology , Female , Male , Middle Aged , Tissue and Organ Procurement/statistics & numerical data , Tissue Donors/supply & distribution , Tissue Donors/statistics & numerical data , Adult , Survival Rate , Prognosis , Practice Patterns, Physicians'/statistics & numerical dataABSTRACT
Type 2 diabetes (T2D) is a chronic multifactorial disease characterized by a combination of insulin resistance and impaired glucose regulation. The alleviative effects of probiotics on T2D have been widely studied. However, studies on the effects of postbiotics, known as inactivated probiotics, on dairy products are limited. This study aimed to evaluate the effectiveness of postbiotic Lactiplantibacillus plantarum LRCC5314 in milk powder (MP-LRCC5314) in a stress-induced T2D (stress-T2D) mouse model. Compared with probiotic MP-LRCC5314, postbiotic MP-LRCC5314 significantly influenced stress-T2D-related factors. The administration of heat-killed MP-LRCC5314 reduced corticosterone levels, increased short-chain fatty acid production by modulating gut microbiota, and regulated immune response, glucose metabolism, stress-T2D-related biomarkers in the brain, gut, and adipose tissues, as well as glucose and insulin sensitivity. In addition, heat-killed MP-LRCC5314 treatment led to a decrease in pro-inflammatory cytokine levels and an increase in anti-inflammatory cytokine levels. Overall, these findings suggest that adding postbiotic MP-LRCC5314 to milk powder could serve as a potential supplement for stress-T2D mitigation.
Subject(s)
Diabetes Mellitus, Type 2 , Milk , Probiotics , Animals , Mice , Diabetes Mellitus, Type 2/veterinary , Lactobacillus plantarumABSTRACT
Background: The role of donor age in liver transplantation (LT) outcomes for hepatocellular carcinoma (HCC) is controversial. Given the significant risk of HCC recurrence post-LT, optimizing donor/recipient matching is crucial. This study reassesses the impact of young donors on LT outcomes in patients with HCC. Methods: A retrospective review of 11 704 LT cases from the United Network for Organ Sharing database (2012-2021) was conducted. The study focused on the effect of donor age on recurrence-free survival, using hazard associated with LT for HCC (HALT-HCC) and Metroticket 2.0 scores to evaluate post-LT survival in patients with HCC. Results: Of 4706 cases with young donors, 11.0% had HCC recurrence or death within 2 y, and 18.3% within 5 y. These outcomes were comparable with those of non-young donors. A significant correlation between donor age and post-LT recurrence or mortality (Pâ =â 0.04) was observed, which became statistically insignificant after tumor-related adjustments (Pâ =â 0.32). The Kaplan-Meier curve showed that recipients with lower HALT-HCC scores (<9) and Metroticket 2.0 scores (<2.2) significantly benefited from young donors, unlike those exceeding these score thresholds. Cox regression analysis showed that donor age significantly influenced outcomes in recipients below certain score thresholds but was less impactful for higher scores. Conclusions: Young donors are particularly beneficial for LT recipients with less aggressive HCC, as indicated by their HALT-HCC and Metroticket 2.0 scores. These findings suggest strategically allocating young donors to recipients with less aggressive tumor profiles, which could foster more efficient use of the scarce donor supply and potentially enhance post-LT outcomes.
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This study evaluated the effects of 25-hydroxycholecalciferol (25-OHD) on performance, gut health, and bone quality of broilers fed with reduced calcium (Ca) and phosphorus (P) diet during Eimeria spp. challenge. A total of 576 fourteen-day-old Cobb 500 male chicks were randomly distributed in a 2 × 2 × 2 factorial arrangement, with 6 replicates of 12 birds each. The main factors were 25-OHD level (0 or 3,000 IU/kg of feed), mineral level (0.84% of Ca/0.42% of P, the levels recommended for the grower phase (NOR) or 0.64% of Ca/0.22% of P (RED), and mid-high mixed Eimeria challenge or nonchallenge. 25-OHD improved phosphorus retention (P = 0.019), bone ash weight (P = 0.04), cortical bone trabecular connectivity (P = 0.043) during coccidiosis. For birds fed with reduced mineral levels, 25-OHD supplementation increased bone ash weight (P = 0.04). However, 25-OHD did not improve bone ash weight when birds were challenged and fed with reduced mineral levels. The dietary 3,000 IU of 25-OHD supplementation did not improve performance or gut morphology but support bone health during coccidiosis. Future investigations are needed for better understand 25-OHD role on bone microarchitecture and oxidative metabolism during coccidiosis.
Subject(s)
Coccidiosis , Eimeria , Poultry Diseases , Animals , Male , Chickens , Calcifediol/pharmacology , Dietary Supplements , Phosphorus , Calcium , Diet/veterinary , Minerals , Coccidiosis/veterinary , Animal Feed/analysis , Poultry Diseases/metabolismABSTRACT
Spontaneous bacterial peritonitis is a life-threatening complication of cirrhosis that can increase healthcare utilization. The impact of albumin administration timing on hospital resource utilization and its optimal timing is unclear, despite its efficacy in improving survival for cirrhosis patients with spontaneous bacterial peritonitis. A retrospective study was conducted to evaluate the influence of the timing of albumin administration on the length of stay and total hospital cost for patients with cirrhosis and spontaneous bacterial peritonitis who require fluid resuscitation. The study utilized de-identified data from Cerner Health Facts® data. Adult inpatients with a diagnosis of cirrhosis and SBP receiving ≥1 antibiotic and fluid resuscitation between January 1, 2009, and April 30, 2018, were included and stratified by albumin administration timing: ≤24 hours from hospital admission ("timely albumin") or >24 hours of admission or no albumin ("non-timely albumin"). We used a Kaplan-Meier curve with log-rank test to evaluate the association between timing of albumin administration and time to hospital discharge and a generalized linear model to examine the association between albumin timing and total hospital costs. We identified 1,308 hospitalizations, of which 301 contained valid cost data. The timely albumin group had a median time to discharge of 6.95 days compared to 7.78 days in the non-timely group (p = 0.02). Cost model showed that receiving timely albumin incurred 16% lower costs (p = 0.027) than patients in the non-timely albumin group. Timely albumin administration with an antibiotic regimen may shorten the length of stay and lower costs, thereby reducing hospital resource utilization in patients with cirrhosis and spontaneous bacterial peritonitis requiring fluid resuscitation.