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BACKGROUND AIMS: Offering LT to frail patients may reduce waitlist mortality but may increase post-LT mortality. LT survival benefit is the concept of balancing these risks. We sought to quantify net survival benefit with LT by liver frailty index (LFI). APPROACH RESULTS: We analyzed data in the multi-center Functional Assessment in LT (FrAILT) Study from 2012-2021. Pre-LT cohort included ambulatory patients with cirrhosis awaiting LT, without hepatocellular carcinoma; post-LT cohort included those who underwent LT. Primary outcomes were pre-LT and post-LT mortality. We computed 1-, 3-, and 5-year restricted mean survival times (RMST) from adjusted Cox models. Survival benefit was calculated as net gain in life-years with LT. Pre-LT cohort included 2628 patients: median MELDNa was 18 (IQR 14-22); 731 (28%) were frail; 440 (17%) died pre-LT. Post-LT cohort included 1335 patients: median MELDNa was 20 (IQR 14-24); 325 (24%) were frail; 103 (8%) died post-LT. Pre-LT RMST decreased substantially as LFI increased. Post-LT RMST also decreased as LFI increased but only modestly. There was no LFI threshold at which pre-LT and post-LT RMST intersected-patients had net survival benefit at all LFI values. CONCLUSION: Pre-LT and, to a lesser degree, post-LT mortality increased as LFI increased. Transplant offered a survival benefit at all LFI values, driven by a reduction in pre-LT mortality. No threshold of LFI was identified at which the risk of post-LT mortality exceeded pre-LT mortality. LT offers net survival benefit even in the presence of advanced frailty among those selected for LT.
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Background: Gastrointestinal bleeding (GIB) is a common complication after placement of a left ventricular assist device (LVAD). Some institutions attempt to mitigate post-LVAD GIB using preoperative endoscopy. Our study evaluated whether preoperative endoscopy was associated with a lower risk of post-LVAD GIB. Methods: This was a multicenter cohort study of patients who underwent LVAD insertion from 2010-2019 at 3 academic sites. A total of 398 study participants were categorized based on whether they underwent preoperative endoscopy or not. The follow-up period was 1 year and the primary outcome was GIB. Secondary outcomes were severe bleeding and intraprocedural complications. Results: A total of 114 patients experienced GIB within 1 year, with a higher rate in the endoscopy cohort (36.4% vs. 24.8%, P=0.015). After adjusting for covariables, the endoscopy cohort remained at increased risk of GIB (adjusted odds ratio 1.77, 95% confidence interval 1.05-2.976; P=0.032). Severe bleeding was common (47.4%). Arteriovenous malformations (48 cases) and peptic ulcer disease (17 cases) were the most identified sources of GIB. Only 1 minor adverse event occurred during preoperative endoscopy. Conclusions: Our study suggests that pre-LVAD endoscopy is associated with a higher risk of GIB post LVAD, despite controlling for confounders. While this was an observational study and may not have captured all confounders, it appears that endoscopic screening may not be warranted.
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The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.
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Hepatic encephalopathy (HE) is a strong predictor of early hospital readmission in patients with cirrhosis. Early hospital readmission increases health care costs and is associated with worse survival. Herein we provide an overview of strategies to prevent hospital readmissions in patients with HE, divided into 3 contexts: (a) acute inpatient, (b) immediate postdischarge, and (c) longitudinal outpatient setting.
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Encefalopatia Hepática , Humanos , Encefalopatia Hepática/terapia , Encefalopatia Hepática/complicações , Readmissão do Paciente , Fatores de Risco , Pacientes Internados , Pacientes Ambulatoriais , Assistência ao Convalescente , Alta do Paciente , Cirrose Hepática/complicaçõesRESUMO
BACKGROUND: Patients with obesity have inferior outcomes after general surgery procedures, but studies evaluating post-liver transplant (LT) outcomes have been limited by small sample sizes or lack of granularity of outcomes. We evaluated the relationship between obesity and post-LT outcomes, including those observed in other populations to be obesity-related. METHODS: Included were 1357 LT recipients prospectively enrolled in the ambulatory pre-LT setting at 8 U.S. CENTERS: Recipient were categorized by body mass index (BMI, kg/m2 ): non-obese (BMI < 30), class 1 obesity (BMI 30-<35), and classes 2-3 obesity (BMI ≥ 35). Post-transplant complications were compared by BMI using Chi-square and rank-sum testing, logistic regression, Kaplan-Meier curves, and Cox regression. RESULTS: Classes 2-3 obesity was associated with higher adjusted odds than non-obesity of venous thrombosis [adjusted odds ratio (aOR) 2.06, 95% CI 1.01-4.23, p = .047] and wound dehiscence (aOR 2.45, 95% CI 1.19-5.06, p = .02). Compared with non-obese recipients, post-LT hospital stay was significantly longer for recipients with classes 2-3 obesity [p = .01; median (Q1-Q3) 9 (6-14) vs. 8 (6-12) days) or class 1 obesity [p = .002; 9 (6-14) vs. 8 (6-11) days]. Likelihood of ICU readmission, infection, discharge to a non-home facility, rejection, 30-day readmission, and 1-year readmission were similar across BMI categories (all p > .05). CONCLUSION: Compared to non-obese recipients, obese recipients had similar post-LT survival but longer hospital stay and higher likelihood of wound dehiscence and venous thrombosis. These findings underscore that obesity alone should not preclude LT, but recipients with obesity should be monitored for obesity-related complications such as wound dehiscence and venous thrombosis.
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Transplante de Fígado , Trombose Venosa , Humanos , Índice de Massa Corporal , Transplante de Fígado/efeitos adversos , Obesidade/etiologia , Complicações Pós-Operatórias/etiologia , Trombose Venosa/complicações , Estudos Retrospectivos , Resultado do Tratamento , Fatores de RiscoRESUMO
BACKGROUND: Older adults have higher healthcare utilization after liver transplantation (LT), yet objective risk stratification tools in this population are lacking. We evaluated the Liver Frailty Index (LFI) as one potential tool. METHODS: Ambulatory LT candidates ≥65 years without hepatocellular carcinoma (HCC) who underwent LT from 1/2012 to 6/2022 at 8 U.S. centers were included. Estimates of the difference in median using quantile regression were used to assess the adjusted association between LFI and hospitalized days within 90 days post-LT. RESULTS: Of 131 LT recipients, median (interquartile range [IQR]) (1st -3rd quartiles) age was 68 years (66-70); median pre-LT MELD-Na was 19 (15-24). Median LFI was 4.1 (3.6-4.7); 27% were frail (LFI≥4.5). Median hospitalized days within 90 days post-LT was 11 (7-20). Compared with non-frail patients, frail patients were hospitalized for a median of 5 days longer post-LT (95% CI .30-9.7, p = .04). Each .5 unit increase in pre-LT LFI was associated with an increase of 1.16 days (95%CI .42-2.69, p = .02) in hospitalized days post-LT. CONCLUSION: Among older adults undergoing LT, frailty was associated with more hospitalized days within 90 days after LT. The LFI can identify older adults who might benefit from pre-LT or early post-LT programs which may reduce post-LT healthcare utilization, such as early rehabilitation or post-hospital discharge programs.
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Carcinoma Hepatocelular , Fragilidade , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Idoso , Carcinoma Hepatocelular/patologia , Fragilidade/epidemiologia , Neoplasias Hepáticas/patologia , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
OBJECTIVE: To evaluate differences in quantitative features between poorly versus highly rated patient ratings of radiology reports. METHODS: A HIPAA-compliant, IRB-waived study was performed from October 2019 to June 2021. Patients completed an optional 2-question survey ("How helpful was the report?" with a 5-star scale and an open text box) embedded into the patient portal, and reports were assessed for readability and brevity. Quantitative analyses were performed between poorly (≤3 stars) and highly rated (>3 stars) CT and MRI reports, including the use of structured reporting, number of words, words per sentence, Flesch Reading Ease, and Flesh-Kincaid Grade level within the findings and impression sections of the radiology reports. A two-tailed nonparametric Mann U Whitney test was performed for continuous variables and Chi2 for categorical variables. RESULTS: Of the 490 responses, all 135 evaluating CT or MR were included (27%). 106/135 (78%) of the patients gave high ratings (score of 4 or 5). 46/135 (34%), the radiology reports were in a structured format. The proportion of highly rated reports were significantly higher for structured than freeform reports (93.5 vs. 70.8%, p = 0.002). In the findings section, highly rated reports had a lower Flesch Reading Ease score than poorly rated reports (19.6 vs. 28.9, p <0.01). No significant differences were observed between number of words (p=0.27), words per sentence (p=0.94), and Flesh-Kincaid Grade level (p=0.09) in the findings section. In the impression section, no differences were observed between highly vs. poorly rated reports among the measured parameters. CONCLUSION: Patients preferred highly rated reports that were structured and had lower Flesch Reading Ease scores in the findings section.
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Imageamento por Ressonância Magnética , Radiologia , Humanos , Compreensão , LeituraRESUMO
BACKGROUND: Expedited liver transplant evaluations of critically ill patients can be challenging due to limited time for data gathering and psychosocial evaluation. AIMS: To compare clinical outcomes between expedited and traditional transplant evaluation patients and assess for differences in outpatient resource utilization and staff burden between groups. DESIGN: Adult liver transplant recipients who underwent transplant from 2015 to 2019 were included. Expedited evaluation was defined as time from initiating transplant evaluation to transplant listing <2 weeks. Primary outcomes included rates of graft rejection, graft failure, and death within 1-year posttransplant. Secondary outcomes included number of acute care visits, office visits, and medical record documentation made by transplant staff within 1-year posttransplant. Outcomes were compared using Cox regression models. RESULTS: Of the 335 patients included, 92 (27.5%) were expedited and 243 (72.5%) were traditional. Expedited patients were significantly younger, had greater MELD scores, and required more inpatient care and life support at time of transplant. There was no significant difference in risk of graft rejection (HR 1.3, P = .4), graft failure (HR 1.3, P = .6), or mortality (HR 1.0, P = .9) between groups. Expedited transplant was not associated with increased healthcare or staff utilization: acute care visits (rate ratio 0.9, P = .7), office visits (ß = -1.05, P = .2), and medical record documentation (ß = 3.4, P = 0.4). CONCLUSIONS: Despite being more critically ill, patients requiring expedited transplant evaluation have favorable outcomes after transplant and do not require more intensive staff time and resources compared to traditional candidates.
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Transplante de Fígado , Transplantes , Adulto , Humanos , Estado Terminal , Modelos de Riscos Proporcionais , Rejeição de Enxerto/prevenção & controle , Transplantados , Sobrevivência de Enxerto , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT). METHODS: Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n = 36) or TACE (n = 40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2 Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost. RESULTS: Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54-0.86, and 65%, 95% CI, 0.52-0.83 (p = .80), however, median PFS was improved for PBT versus TACE (not reached vs. 12 months, p = .002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78-17.9, p = .003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p < .001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT. CONCLUSIONS: PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Terapia com Prótons , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Prótons , Quimioembolização Terapêutica/métodos , Resultado do Tratamento , Estudos RetrospectivosRESUMO
The 4.1-billion-year-old meteorite Allan Hills 84001 (ALH 84001) may preserve a magnetic record of the extinct martian dynamo. However, previous paleomagnetic studies have reported heterogeneous, nonunidirectional magnetization in the meteorite at submillimeter scales, calling into question whether it records a dynamo field. We use the quantum diamond microscope to analyze igneous Fe-sulfides in ALH 84001 that may carry remanence as old as 4.1 billion years (Ga). We find that individual, 100-µm-scale ferromagnetic mineral assemblages are strongly magnetized in two nearly antipodal directions. This suggests that the meteorite recorded strong fields following impact heating at 4.1 to 3.95 Ga, after which at least one further impact heterogeneously remagnetized the meteorite in a nearly antipodal local field. These observations are most simply explained by a reversing martian dynamo that was active until 3.9 Ga, thereby implying a late cessation for the martian dynamo and potentially documenting reversing behavior in a nonterrestrial planetary dynamo.
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Importance: Frailty has been recognized as a risk factor for mortality after liver transplant (LT) but little is known of its association with functional status and health-related quality of life (HRQL), termed global functional health, in LT recipients. Objective: To evaluate the association between pre-LT and post-LT frailty with post-LT global functional health. Design, Setting, and Participants: This prospective cohort study was conducted at 8 US LT centers and included adults who underwent LT from October 2016 to February 2020. Exposures: Frail was defined by a pre-LT Liver Frailty Index (LFI) score of 4.5 or greater. Main Outcomes and Measures: Global functional health at 1 year after LT, assessed using surveys (Short Form-36 [SF-36; summarized by physical component scores (PFC) and mental component summary scores (MCS)], Instrumental Activities of Daily Living scale) and performance-based tests (LFI, Fried Frailty Phenotype, and Short Physical Performance Battery). Results: Of 358 LT recipients (median [IQR] age, 60 [53-65] years; 115 women [32%]; 25 [7%] Asian/Pacific Islander, 21 [6%] Black, 54 [15%] Hispanic White, and 243 [68%] non-Hispanic White individuals), 68 (19%) had frailty pre-LT. At 1 year post-LT, the median (IQR) PCS was lower in recipients who had frailty vs those without frailty pre-LT (42 [31-53] vs 50 [38-56]; P = .002), but the median MCS was similar. In multivariable regression, pre-LT frailty was associated with a -5.3-unit lower post-LT PCS (P < .001), but not MCS. The proportion who had difficulty with 1 or more Instrumental Activities of Daily Living (21% vs 10%) or who were unemployed/receiving disability (38% vs 29%) was higher in recipients with vs without frailty. In a subgroup of 210 recipients with LFI assessments 1 year post-LT, 13% had frailty at 1 year post-LT. Recipients who had frailty post-LT reported lower adjusted SF-36-PCS scores (coefficient, -11.4; P < .001) but not SF-36-MCS scores. Recipients of LT who had frailty vs those without frailty 1 year post-LT also had worse median (IQR) Fried Frailty Phenotype scores (1 [1-2] vs 1 [0-1]) and higher rates of functional impairment by a Short Physical Performance Battery of 9 or less (42% vs 20%; P = .01). Conclusions and Relevance: In this cohort study, pre-LT frailty was associated with worse global functional health 1 year after LT. The presence of frailty after LT was also associated with worse HRQL in physical, but not mental, subdomains. These data suggest that interventions and therapeutics that target frailty that are administered before and/or early post-LT may help to improve the health and well-being of LT recipients.
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Fragilidade , Transplante de Fígado , Humanos , Feminino , Qualidade de Vida , Fragilidade/complicações , Estudos de Coortes , Atividades Cotidianas , Estudos ProspectivosRESUMO
Lipid biosynthesis plays a vital role in living cells and has been increasingly engineered to overproduce various lipid-based chemicals. However, owing to the tightly constrained and interconnected nature of lipid biosynthesis, both understanding and engineering of lipid metabolism remain challenging, even with the help of mathematical models. Here we report the development of a kinetic metabolic model of lipid metabolism in Saccharomyces cerevisiae that integrates fatty acid biosynthesis, glycerophospholipid metabolism, sphingolipid metabolism, storage lipids, lumped sterol synthesis, and the synthesis and transport of relevant target-chemicals, such as fatty acids and fatty alcohols. The model was trained on lipidomic data of a reference S. cerevisiae strain, single knockout mutants, and lipid overproduction strains reported in literature. The model was used to design mutants for fatty alcohol overproduction and the lipidomic analysis of the resultant mutant strains coupled with model-guided hypothesis led to discovery of a futile cycle in the triacylglycerol biosynthesis pathway. In addition, the model was used to explain successful and unsuccessful mutant designs in metabolic engineering literature. Thus, this kinetic model of lipid metabolism can not only enable the discovery of new phenomenon in lipid metabolism but also the engineering of mutant strains for overproduction of lipids.
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Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Metabolismo dos Lipídeos/genética , Ácidos Graxos , Engenharia MetabólicaRESUMO
Chronic liver disease (CLD) is a progressive illness with high symptom burden and functional and cognitive impairment, often with comorbid mental and substance use disorders. These factors lead to significant deterioration in quality of life, with immense burden on patients, caregivers, and healthcare. The current healthcare system in the United States does not adequately meet the needs of patients with CLD or control costs given the episodic, reactive, and fee-for-service structure. There is also a need for clinical and financial accountability for CLD care. In this context, we describe the key elements required to shift the CLD care paradigm to a patient-centered and value-based system built upon the Porter model of value-based health care. The key elements include (1) organization into integrated practice units, (2) measuring and incorporating meaningful patient-reported outcomes, (3) enabling technology to allow innovation, (4) bundled care payments, (5) integrating palliative care within routine care, and (6) formalizing centers of excellence. These elements have been shown to improve outcomes, reduce costs, and improve overall patient experience for other chronic illnesses and should have similar benefits for CLD. Payers need to partner with providers and systems to build upon these elements and help align reimbursements with patients' values and outcomes. The national organizations such as the American Association for Study of Liver Diseases need to guide key stakeholders in standardizing these elements to optimize patient-centered care for CLD.
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Hepatopatias , Qualidade de Vida , Humanos , Estados Unidos , Atenção à Saúde , Cuidados Paliativos , Assistência Centrada no Paciente , Hepatopatias/terapiaRESUMO
Metabolic engineering aims to improve the production of economically valuable molecules through the genetic manipulation of microbial metabolism. While the discipline is a little over 30 years old, advancements in metabolic engineering have given way to industrial-level molecule production benefitting multiple industries such as chemical, agriculture, food, pharmaceutical, and energy industries. This review describes the design, build, test, and learn steps necessary for leading a successful metabolic engineering campaign. Moreover, we highlight major applications of metabolic engineering, including synthesizing chemicals and fuels, broadening substrate utilization, and improving host robustness with a focus on specific case studies. Finally, we conclude with a discussion on perspectives and future challenges related to metabolic engineering.
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Indústrias , Engenharia MetabólicaRESUMO
Content available: Audio Recording.
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Aim: Our main objectives were to compare the effects of Rejuveinix (RJX), dexamethasone (DEX) and their combination on the severity of sepsis and survival outcome in an animal model of fatal sepsis. Methods: We used the LPS plus D-galactosamine mouse model of sepsis to compare the anti-inflammatory activities of RJX, dexamethasone and a combination of RJX plus DEX. Additionally, we examined the clinical feasibility and tolerability of combining RJX with DEX in COVID-19 patients in a clinical phase I study. Data were analyzed using standard methods. Results & conclusion: RJX exhibited potent anti-inflammatory activity in the murine sepsis model. The combination of RJX plus DEX was more effective than either agent alone, decreased the inflammatory cytokine responses and associated organ damage, and improved the survival outcome in mice. In the phase I clinical study, RJX plus DEX was well tolerated by COVID-19 patients.
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Anti-Inflamatórios , Tratamento Farmacológico da COVID-19 , Sepse , Animais , Anti-Inflamatórios/uso terapêutico , Ácido Ascórbico , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Combinação de Medicamentos , Sulfato de Magnésio , Camundongos , Niacinamida , Ácido Pantotênico , Piridoxina , Riboflavina , Sepse/tratamento farmacológico , TiaminaRESUMO
Background: Frailty commonly complicates cirrhosis and is associated with poorer outcomes. While patients with cirrhosis may be sedentary, there are few comprehensive descriptions of their physical activity (PA) patterns related to frailty. Our aim was to identify PA characteristics that may be used in interventions to improve PA and reduce frailty. Methods: In a cross-sectional cohort study, forty patients with cirrhosis (mean age 63; 30 nonfrail, 10 frail) wore an accelerometer/thermal sensing armband for 7 days. Postural status (e.g., upright movement, upright sedentary, lying down), Metabolic Equivalent of Tasks (METs) and active bouts were identified. Results: Patients were highly sedentary most of the time (89 ± 7% and 85 ± 10% of the day, in frail and nonfrail cirrhotics, respectively). Compared with nonfrail cirrhotics, frail patients spent significantly shorter amount of time moving in an upright position (7% ± 5 vs. 12% ± 5, P = 0.013 in frail and nonfrail cirrhotics, respectively), had significantly fewer and shorter durations of active bouts per day (number of active bouts: 9 ± 12 vs. 19 ± 14; duration: 13.2 ± 1.5 min and 15.9 ± 2.6 min in frail and nonfrail cirrhotics, respectively), and had a lower amount of steps per wear time hours (41.7 ± 37.1 vs. 116.8 ± 85.4, P = 0.003 in frail and nonfrail, respectively). Traditional measures such as METs or aerobic bouts did not differ between groups. Conclusions: Active bout measures, as opposed to more traditional measures such as METs, differentiate between frail and nonfrail cirrhotics suggesting they may be used to assess changes resulting from targeted interventions to improve physical activity.