Search

Acute-on-chronic liver failure (ACLF) has come a long way as a clinical concept within the hepatology and liver transplant communities. Though the term was proposed in 1995, the first recognition of the entity along with a consensus definition emerged in 2009. Subsequently, the entity has sparked great interest, inspired several consensus conferences, and inspired national societies to form professional ACLF affinity groups (eg, special interest group). Multicenter consortia have been established all over the world to study this condition, including the North American Consortium for the Study of End-Stage Liver Disease, Chronic Liver Failure consortium, Asian Pacific Association for the Study of Liver Diseases ACLF Research Consortium, Chronic Liver disease Evolution And Registry for Events and Decompensation, and the LiverHope Consortium. Collectively, these consortia have enrolled tens of thousands of patients with or at risk for ACLF across dozens of countries and characterized in detail the predictors, pathogenesis, and progression of patients with ACLF. Perhaps most importantly, they have produced essential data characterizing the excess morbidity and mortality that patients with ACLF face, making a compelling case for the urgent need for therapeutic strategies for this condition.

This study analyzed qualitative and quantitative survey responses from 51 pediatric primary sclerosing cholangitis (PSC) patients and caregivers using the PSC Partners Patient Registry–Our Voicessurvey. The most common symptoms reported by children/caregivers include: fatigue (71%), abdominal pain (69%), anxiety (59%), appetite loss (51%), insomnia (49%), and pruritus (45%). When experiencing symptoms at their worst, over half of patients/caregivers reported limitations in physically demanding activities (67%), work/school duties (63%), social life activities (55%), and activities for fun or exercise (53%). Over half of patients/caregivers expressed willingness to participate in clinical trials, however none reported ever participating in trials for new or investigational PSC drugs. This study revealed a substantial patient/caregiver‐reported symptom burden for children with PSC that impacts quality of life and limits access to clinical trials. Future efforts should focus on developing patient‐centered clinical endpoints for PSC trials, increasing trial availability for pediatric PSC patients, and reducing logistical barriers to trial involvement. Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by symptoms such as intractable pruritus, abdominal pain, fatigue, anxiety, and depression.There are no effective or US Food and Drug Administration‐approved disease‐modifying therapies available for PSC. Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by symptoms such as intractable pruritus, abdominal pain, fatigue, anxiety, and depression. There are no effective or US Food and Drug Administration‐approved disease‐modifying therapies available for PSC. Children with PSC experience significant symptom burden that negatively impacts their quality of life.There is a paucity of research studies directly aimed at pediatric PSC and improving symptoms or interrupting the natural history of the disease. Children with PSC experience significant symptom burden that negatively impacts their quality of life. There is a paucity of research studies directly aimed at pediatric PSC and improving symptoms or interrupting the natural history of the disease.

Neighborhood contextual factors are associated with liver transplant outcomes. We analyzed associations between neighborhood‐level socioeconomic status and healthcare utilization for pediatric liver transplant recipients. We merged the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases and included liver transplant recipients ≤21 years hospitalized between January 2004 and May 2022. Outcomes were annual inpatient bed‐days, risk of hospitalizations, and risk of liver biopsies. The primary exposure was zip code‐based neighborhood income at transplant. We applied causal inference for variable selection in multivariable analysis. We modeled annual inpatient bed‐days with mixed‐effect zero‐inflated Poisson regression, and rates of hospitalization and liver biopsy with a Cox‐type proportional rate model. We included 1006 participants from 29 institutions. Children from low‐income neighborhoods were more likely to be publicly insured (67% vs. 46%), Black (20% vs. 12%), Hispanic (30% vs. 17%), and have higher model for end‐stage liver disease/pediatric end‐stage liver disease model scores at transplant (17 vs. 13) than the remaining cohort. We found no differences in inpatient bed‐days or rates of hospitalization across neighborhood groups. In univariable analysis, low‐income neighborhoods were associated with increased rates of liver biopsy (rate ratio [RR]: 1.57, 95% confidence interval [CI]: 1.04−2.34, p= 0.03). These findings persisted after adjusting for insurance, race, and ethnicity (RR: 1.86, 95% CI: 1.23−2.83, p< 0.01). Children from low‐income neighborhoods undergo more liver biopsies than other children. These procedures are invasive and potentially preventable. In addition to improving outcomes, interventions to mitigate health inequities among liver transplant recipients may reduce resource utilization. Social determinants of health, including a child's neighborhood context, are closely tied to long‐term outcomes in pediatric liver transplants.Children living in socioeconomically disadvantaged neighborhoods have increased rates of medication nonadherence, graft failure, and death. Social determinants of health, including a child's neighborhood context, are closely tied to long‐term outcomes in pediatric liver transplants. Children living in socioeconomically disadvantaged neighborhoods have increased rates of medication nonadherence, graft failure, and death. Children from low‐income neighborhoods experience higher rates of liver biopsy post‐transplant. These procedures are invasive and potentially preventable.In addition to improving pediatric outcomes, interventions to mitigate health inequities in liver transplants may reduce resource utilization. Children from low‐income neighborhoods experience higher rates of liver biopsy post‐transplant. These procedures are invasive and potentially preventable. In addition to improving pediatric outcomes, interventions to mitigate health inequities in liver transplants may reduce resource utilization.

Children exposed to disproportionately higher levels of air pollution experience worse health outcomes. In this population-based, observational registry study, we examine the association between air pollution and graft failure/death in children following liver transplantation (LT) in the US. We modeled the associations between air pollution (PM2.5) levels localized to the patient’s ZIP code at the time of transplant and graft failure or death using Cox proportional-hazards models in pediatric LT recipients aged <19 years in the US from 2005-2015. In univariable analysis, high neighborhood PM2.5was associated with a 56% increased hazard of graft failure/death (HR: 1.56; 95% CI: 1.32, 1.83; P< .001). In multivariable analysis, high neighborhood PM2.5was associated with a 54% increased risk of graft failure/death (HR: 1.54; 95% CI: 1.29, 1.83; P< .001) after adjusting for race as a proxy for racism, insurance status, rurality, and neighborhood socioeconomic deprivation. Children living in high air pollution neighborhoods have an increased risk of graft failure and death posttransplant, even after controlling for sociodemographic variables. Our findings add further evidence that air pollution contributes to adverse health outcomes for children posttransplant and lay the groundwork for future studies to evaluate underlying mechanisms linking PM2.5to adverse LT outcomes.

Frailty is classically associated with advanced age but is also an important predictor of clinical outcomes in comparatively young adults with cirrhosis. We examined the association of biological aging with frailty and post-transplant outcomes in a pilot of adults with cirrhosis undergoing liver transplantation (LT). Frailty was measured via the Liver Frailty Index (LFI). The primary epigenetic clock DNA methylation (DNAm) PhenoAge was calculated from banked peripheral blood mononuclear cells; we secondarily explored two first-generation clocks (Hannum; Horvath) and two additional second-generation clocks (GrimAge; GrimAge2). Twelve adults were included: seven frail (LFI ≥ 4.4, mean age 55 years) and five robust (LFI < 3.2, mean age 55 years). Mean PhenoAge age acceleration (AgeAccel) was + 2.5 years (P= 0.23) for frail versus robust subjects. Mean PhenoAge AgeAccel was + 2.7 years (P= 0.19) for subjects who were readmitted or died within 30 days of discharge post-LT versus those without this outcome. When compared with first-generation clocks, the second-generation clocks demonstrated greater average AgeAccel for subjects with frailty or poor post-LT outcomes. Measuring biological age using DNAm-derived epigenetic clocks is feasible in adults undergoing LT. While frail and robust subjects had the same average chronologicalage, average biologicalage as measured by second-generation epigenetic clocks tended to be accelerated among those who were frail or experienced a poor post-LT outcome. These results suggest that frailty in these relatively young subjects with cirrhosis may involve similar aging mechanisms as frailty classically observed in chronologically older adults and warrant validation in a larger cohort.

The widespread move to online schooling during the COVID-19 crisis meant that parents played a significant role in educating their children. However, there is a paucity of research relating to parents’ perceptions of online and remote learning designs. This study used multiple regression analyses and thematic analysis of parent survey responses during COVID-19 to examine which online tasks reduced parental stress and student difficulty, increased student autonomy and learning, and increased parental satisfaction. A key finding was that digital creativity tasks were related to lower levels of parental stress, lower student difficulty, greater student autonomy and greater parent satisfaction with school support. Parents also preferred more web-conferencing lessons and offline tactile activities, and less digital worksheets. These findings have implications for educator-parent collaboration and for remote learning broadly.

Aims and methodRecently, the Health of the Nation Outcome Scales 65+ (HoNOS65+) were revised. Twenty-five experts from Australia and New Zealand completed an anonymous web-based survey about the content validity of the revised measure, the HoNOS Older Adults (HoNOS OA).ResultsAll 12 HoNOS OA scales were rated by most (≥75%) experts as ‘important’ or ‘very important’ for determining overall clinical severity among older adults. Ratings of sensitivity to change, comprehensibility and comprehensiveness were more variable, but mostly positive. Experts’ comments provided possible explanations. For example, some experts suggested modifying or expanding the glossary examples for some scales (e.g. those measuring problems with relationships and problems with activities of daily living) to be more older adult-specific.Clinical implicationsExperts agreed that the HoNOS OA measures important constructs. Training may need to orient experienced raters to the rationale for some revisions. Further psychometric testing of the HoNOS OA is recommended.

The informal caregiver plays a critical role in supporting patients with various end-stage diseases throughout the solid organ transplantation journey. Caregiver responsibilities include assistance with activities of daily living, medication management, implementation of highly specialized treatments, transportation to appointments and treatments, and health care coordination and navigation. The demanding nature of these tasks has profound impacts across multiple domains of the caregiver’s life: physical, psychological, financial, logistical, and social. Few interventions targeting caregiver burden have been empirically evaluated, with the majority focused on education or mindfulness-based stress reduction techniques. Further research is urgently needed to develop and evaluate interventions to improve caregiver burden and outcomes for the patient–caregiver dyad.

Solid organ transplantation provides the best treatment for end-stage organ failure, but significant sex-based disparities in transplant access exist. On June 25, 2021, a virtual multidisciplinary conference was convened to address sex-based disparities in transplantation. Common themes contributing to sex-based disparities were noted across kidney, liver, heart, and lung transplantation, specifically the existence of barriers to referral and wait listing for women, the pitfalls of using serum creatinine, the issue of donor/recipient size mismatch, approaches to frailty and a higher prevalence of allosensitization among women. In addition, actionable solutions to improve access to transplantation were identified, including alterations to the current allocation system, surgical interventions on donor organs, and the incorporation of objective frailty metrics into the evaluation process. Key knowledge gaps and high-priority areas for future investigation were also discussed.

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 &lt; .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 &lt; .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.

There is much controversy regarding enhanced recovery for recipients of liver transplants from deceased and living donors. The objectives of this Review were to summarise current knowledge on individual enhanced recovery elements on short-term outcomes, identify key components for comprehensive pathways, and create internationally accepted guidelines on enhanced recovery for liver-transplant recipients. The ERAS4OLT.org collaborative partnered by the International Liver Transplantation Society performed systematic literature reviews on the effect of 32 relevant enhanced perioperative recovery elements on short-term outcomes, and global specialists prepared expert statements on deceased and living donor liver transplantation. The Grading Recommendations, Assessment, Development and Evaluations approach was used for rating of quality of evidence and grading of recommendations. A virtual international consensus conference was held in January, 2022, in which results were presented, voted on by the audience, and discussed by an independent international jury of eight members, applying the Danish model of consensus. 273 liver transplantation specialists from 30 countries prepared expert statements on elements of enhanced recovery for liver transplantation based on the systematic literature reviews. The consensus conference yielded 80 final recommendations, covering aspects of enhanced recovery for preoperative assessment and optimisation, intraoperative surgical and anaesthetic conduct, and postoperative management for the recipients of liver transplants from both deceased and living donors, and for the living donor. The recommendations represent a comprehensive overview of the relevant elements and areas of enhanced recovery for liver transplantation. These internationally established guidelines could direct the development of enhanced recovery programmes worldwide, allowing adjustments according to local resources and practices.

“Sarcopenic obesity” refers to a condition of low muscle mass in the context of obesity, though may be difficult to assess in patients with cirrhosis who are acutely ill. We aimed to define sarcopenic visceral obesity (SVO) using CT‐based skeletal muscle index (SMI) and visceral‐to‐subcutaneous adipose tissue ratio (VSR) to examine its association with post‐transplant mortality. We analyzed 116 adult inpatients with cirrhosis who were urgently listed and transplanted between 1/2005 and 12/2017 at 4 North American transplant centers. SVO was defined as patients with sarcopenia (SMI <50 cm2/m2in men and <39 cm2/m2in women) and visceral obesity (VSR ≥ 1.54 in men and ≥1.37 in women). The percentage who met criteria for sarcopenia, visceral obesity, and SVO were 45%, 42%, and 20%, respectively. Cumulative rates of post‐transplant mortality were higher in patients with SVO compared to patients with sarcopenia or visceral obesity alone at 36 months (39% vs. 14% vs. 8%) [logrank p = .01]. In univariable regression, SVO was associated with post‐transplant mortality (HR 2.92, 95%CI 1.04–8.23) and remained significant after adjusting for age, sex, diabetes, encephalopathy, hepatocellular carcinoma, and MELD‐Na (HR 3.50, 95%CI 1.10–11.15). In conclusion, SVO is associated with increased post‐transplant mortality in acutely ill patients with cirrhosis. In acutely ill patients with cirrhosis, concordance of sarcopenia and visceral obesity, as measured by computed tomography, is associated with worst post‐transplant mortality than either condition alone.

Elevated p53 expression is associated with several kidney diseases including diabetic nephropathy (DN). However, the mechanisms are unclear. We report that expression levels of transforming growth factor-β1 (TGF-β), p53, and microRNA-192 (miR-192) are increased in the renal cortex of diabetic mice, and this is associated with enhanced glomerular expansion and fibrosis relative to nondiabetic mice. Targeting miR-192 with locked nucleic acid--modified inhibitors in vivo decreases expression of p53 in the renal cortex of control and streptozotocin-injected diabetic mice. Furthermore, mice with genetic deletion of miR-192 in vivo display attenuated renal cortical TGF-β and p53 expression when made diabetic, and have reduced renal fibrosis, hypertrophy, proteinuria, and albuminuria relative to diabetic wild-type mice. In vitro promoter regulation studies show that TGF-β induces reciprocal activation of miR-192 and p53, via the miR-192 target Zeb2, leading to augmentation of downstream events related to DN. Inverse correlation between miR-192 and Zeb2 was observed in glomeruli of human subjects with early DN, consistent with the mechanism seen in mice. Our results demonstrate for the first time a TGF-β--induced feedback amplification circuit between p53 and miR-192 related to the pathogenesis of DN, and that miR-192--knockout mice are protected from key features of DN., Diabetic nephropathy (DN) is a microvascular complication that leads to kidney dysfunction and end-stage renal disease. DN is characterized by renal glomerular hypertrophy, basement membrane thickening, and fibrosis due to [...]

Women with cirrhosis awaiting liver transplantation are less likely to receive a transplant and more likely to die than men. While differences in body size and estimation of kidney function are well-studied contributors to this gender inequity, what has received relatively little mention as a potential contributing factor is the possibility of implicit bias. Implicit bias is defined as “any unconscious or unacknowledged preference that affects a person’s outlook or behavior.” The undeniable presence of implicit bias, a factor that is known to negatively influence health outcomes for women, within our health care system means that patients interacting within our transplant system may still experience unequal treatment despite our best efforts to modify the allocation system at the national level. Awareness of this additional source of gender-based disparities is the first step. In this article, we posit that implicit bias in liver transplantation may exacerbate the gender inequity in transplant access and provide examples in the literature to support this assertion. Lastly, we offer strategies that could be applied at the individual or the healthcare delivery system levels to help reduce the influence of implicit bias on the gender inequity in liver transplantation.

Background:The long-COVID syndrome (LCS), defined by residual symptoms from acute COVID-19 for <60 days, affects about one-third of all COVID survivors and is an emerging public health challenge. Empirical data about the range of symptoms or the utility of acupuncture alone for the LCS are very limited.Case:This observational case study of a 46-year-old male with LCS was conducted to preliminarily define the range of symptoms, a Traditional Chinese Medicine (TCM) diagnostic structure, and evaluate the potential utility of prescribed acupuncture for LCS.Results:The primary TCM diagnostic patterns from this patient's LCS presentation included Lung Qi and Yin Deficiency, Qi and Blood Stagnation, and Spleen Qi Deficiency with dampness. Acupuncture for this patient was associated with reduced symptoms and signs of LCS.Conclusion:A preliminary TCM diagnostic structure for LCS was defined. Acupuncture appears to have been helpful for a patient with LCS. Further research is needed to demonstrate the efficacy of acupuncture and/or other TCM modalities for LCS.

Introduction:The postacute sequelae of COVID-19 (PASC) is a serious heterogeneous condition that affects a significant minority of those who endured COVID-19. PASC involves multiple body systems and an illness trajectory that has stages now being identified in medical research.Objective:Traditional Chinese Medicine (TCM) and acupuncture are well suited to conceptualize and treat PASC and other postviral conditions. No description of TCM theory and its relationship with modern medical theory about PASC and its illness trajectory currently exists.Conclusion:The authors provide an overview of the potential value of TCM for conceptualizing and treating PASC with a few examples and clarify directions for research.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Neighborhood socioeconomic deprivation is associated with adverse outcomes after pediatric liver transplant. We sought to determine if this relationship varies by transplant center. Using SRTR, we included patients <18 years transplanted 2008–2013 (N = 2804). We matched patient ZIP codes to a deprivation index (range [0,1]; higher values indicate increased socioeconomic deprivation). A center‐level patient‐mix deprivation index was defined by the distribution of patient‐level deprivation. Centers (n = 66) were classified as high or low deprivation if their patient‐mix deprivation index was above or below the median across centers. Center quality was classified as low or high graft failure if graft survival rates were better or worse than the overall 10‐year graft survival rate. Primary outcome was patient‐level graft survival. We used random‐effect Cox models to evaluate center‐level covariates on graft failure. We modeled center quality using stratified Cox models. In multivariate analysis, each 0.1 increase in the patient‐mix deprivation index was associated with increased hazard of graft failure (HR 1.32; 95%CI: 1.05, 1.66). When stratified by center quality, patient‐mix deprivation was no longer significant (HR 1.07, 95%CI: 0.89, 1.28). Some transplant centers care for predominantly high deprivation children and maintain excellent outcomes. Revealing and replicating these centers’ practice patterns should enable more equitable outcomes. The authors explore center‐level effects on outcomes for socioeconomically deprived children and find that certain centers are able to maintain excellent outcomes while caring for predominately socioeconomically deprived children.

One in 10 people die awaiting transplantation from donor shortage. Only half of Americans register as organ donors. In this cross‐sectional study, we evaluated population‐level associations of neighborhood socioeconomic deprivation and racial segregation on organ donor registration rates. We analyzed state identification card demographic and organ donor registration data from 5 states to estimate the association between a neighborhood socioeconomic deprivation index (range [0, 1]; higher values indicate more deprivation) and a racial index of concentration at the extreme (ICE) (range [−1, 1]; lower values indicate predominantly black neighborhoods, higher values indicate predominantly white neighborhoods) on organ donor registration rates within a specified geography (census tract or ZIP code tabulation area [ZCTA]). Among 26 720 738 registrants, 32% of the sample were registered organ donors. At the census tract level, with each 0.1 decrease in the deprivation index, the organ donor registration rate increased by 6.8% (95% confidence interval [CI]: 6.6%, 7.0%). With each 0.1 increase in the racial ICE, the rate increased by 1.5% (95% CI: 1.5%, 1.6%). These associations held true at the ZCTA level. Areas with less socioeconomic deprivation and a higher concentration of white residents have higher organ donor registration rates. Public health initiatives should consider neighborhood context and novel data sources in designing optimal intervention strategies. Increased socioeconomic deprivation and increased racial segregation of neighborhoods are each associated with decreased rates of organ donor designation on state ID cards.

IMPORTANCE: Female liver transplant candidates experience higher rates of wait list mortality than male candidates. Frailty is a critical determinant of mortality in patients with cirrhosis, but how frailty differs between women and men is unknown. OBJECTIVE: To determine whether frailty is associated with the gap between women and men in mortality among patients with cirrhosis awaiting liver transplantation. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study enrolled 1405 adults with cirrhosis awaiting liver transplant without hepatocellular carcinoma seen during 3436 ambulatory clinic visits at 9 US liver transplant centers. Data were collected from January 1, 2012, to October 1, 2019, and analyzed from August 30, 2019, to October 30, 2020. EXPOSURES: At outpatient evaluation, the Liver Frailty Index (LFI) score was calculated (grip strength, chair stands, and balance). MAIN OUTCOMES AND MEASURES: The risk of wait list mortality was quantified using Cox proportional hazards regression by frailty. Mediation analysis was used to quantify the contribution of frailty to the gap in wait list mortality between women and men. RESULTS: Of 1405 participants, 578 (41%) were women and 827 (59%) were men (median age, 58 [interquartile range (IQR), 50-63] years). Women and men had similar median scores on the laboratory-based Model for End-stage Liver Disease incorporating sodium levels (MELDNa) (women, 18 [IQR, 14-23]; men, 18 [IQR, 15-22]), but baseline LFI was higher in women (mean [SD], 4.12 [0.85] vs 4.00 [0.82]; P = .005). Women displayed worse balance of less than 30 seconds (145 [25%] vs 149 [18%]; P = .003), worse sex-adjusted grip (mean [SD], −0.31 [1.08] vs −0.16 [1.08] kg; P = .01), and fewer chair stands per second (median, 0.35 [IQR, 0.23-0.46] vs 0.37 [IQR, 0.25-0.49]; P = .04). In unadjusted mixed-effects models, LFI was 0.15 (95% CI, 0.06-0.23) units higher in women than men (P = .001). After adjustment for other variables associated with frailty, LFI was 0.16 (95% CI, 0.08-0.23) units higher in women than men (P &lt; .001). In unadjusted regression, women experienced a 34% (95% CI, 3%-74%) increased risk of wait list mortality than men (P = .03). Sequential covariable adjustment did not alter the association between sex and wait list mortality; however, adjustment for LFI attenuated the mortality gap between women and men. In mediation analysis, an estimated 13.0% (IQR, 0.5%-132.0%) of the gender gap in wait list mortality was mediated by frailty. CONCLUSIONS AND RELEVANCE: These findings demonstrate that women with cirrhosis display worse frailty scores than men despite similar MELDNa scores. The higher risk of wait list mortality that women experienced appeared to be explained in part by frailty.

We examined whether a key psychological trait—resilience, defined as one's ability to recover quickly from difficulties—contributes to the frail phenotype in patients with cirrhosis. Included were 300 adult patients with cirrhosis who underwent outpatientphysical frailty testing using the Liver Frailty Index and resilience testing using the Connor‐Davidson Resilience Scale (CD‐RISC). The Liver Frailty Index was categorized as robust, prefrail‐robust, prefrail‐frail, and frail; CD‐RISC was categorized using population norms as: least, less, more, and most resilient. Linear regression was used to assess factors associated with frailty (by the Liver Frailty Index per 0.1 unit change). Among the mostresilient, only 10% were frail; among the leastresilient, 29% were frail. In univariable analysis, resilience was strongly associated with the Liver Frailty Index (coef = −0.13 per point increase; 95% confidence interval [CI], −0.20 to −0.60; P< .001) and remained significantly associated with frailty in multivariable adjustment (coef = −0.13, 95% CI −0.19 to −0.07; P< .001). Low resilience is strongly associated with the frail phenotype in patients with cirrhosis. Given that resilience is modifiable, our data suggest that effective interventions to mitigate frailty should include strategies to build resilience in patients with low baseline resilience. Psychological resilience is strongly associated with lower rates of frailty in patients with cirrhosis, suggesting that the Liver Frailty Index may capture aspects of frailty beyond the physical.

AbstractThis paper shows that signals from the offshore China spot market for the Chinese renminbi of the Hong Kong SAR (listed as CNH) directly affect the volatility of share prices of Chinese banks and the overall risks of Chinese banking stability. This is especially so amid heightened uncertainty about global trade or the People’s Republic of China. Thus, the CNH market volatility is a leading indicator of onshore Chinese banking sector volatility. Our results suggest that further offshore exchange market movements arising out of news such as increasing trade friction with the United States will generate greater volatility in the Chinese banking sector. Far from being a shock absorber for the Chinese financial system, the CNH market appears to be a shock transmitter of risk from offshore economic policy uncertainty to the Chinese banking system.

Long‐term outcomes remain suboptimal following pediatric liver transplantation; only one third of children have normal biochemical liver function without immunosuppressant comorbidities 10 years posttransplant. We examined the association between an index of neighborhood socioeconomic deprivation with graft and patient survival using the Scientific Registry of Transplant Recipients. We included children <19 years who underwent liver transplantation between January 1, 2008 to December 31, 2013 (n = 2868). Primary exposure was a neighborhood socioeconomic deprivation index—linked via patient home ZIP code—with a range of 0‐1 (values nearing 1 indicate neighborhoods with greater socioeconomic deprivation). Primary outcome measures were graft failure and death, censored at 10 years posttransplant. We modeled survival using Cox proportional hazards. In univariable analysis, each 0.1 increase in the deprivation index was associated with a 14.3% (95% confidence interval [CI]): 3.8%‐25.8%) increased hazard of graft failure and a 12.5% (95% CI: 2.5%‐23.6%) increased hazard of death. In multivariable analysis adjusted for race, each 0.1 increase in the deprivation index was associated with a 11.5% (95% CI: 1.6%‐23.9%) increased hazard of graft failure and a 9.6% (95% CI: −0.04% to 20.7%) increased hazard of death. Children from high deprivation neighborhoods have diminished graft and patient survival following liver transplantation. Greater attention to neighborhood context may result in improved outcomes for children following liver transplantation. Using a novel index of neighborhood socioeconomic deprivation, the authors find that children from high socioeconomic deprivation neighborhoods are at increased risk of graft failure and death after liver transplant. See McElroy et al's editorial on page 1480.

Split liver transplantation (SLT) is 1 strategy for maximizing the number of deceased donor liver transplants. Recent reports suggest that utilization of SLT in the United States remains low. We examined deceased donor offers that were ultimately split between 2010 and 2014. SLTs were categorized as “primary” and “secondary” transplants. We analyzed allocation patterns and used logistic regression to evaluate factors associated with secondary split discard. Four hundred eighteen livers were split: 54% from adult, 46% from pediatric donors. Of the 227 adult donor livers split, 61% met United Network for Organ Sharing “optimal” split criteria. A total of 770 recipients (418 primary and 352 secondary) were transplanted, indicating 16% discard. Ninety‐two percent of the 418 primary recipients were children, and 47% were accepted on the first offer. Eighty‐seven percent of the 352 secondary recipients were adults, and 7% were accepted on the first offer. Of the 352 pairs, 99% were transplanted in the same region, 36% at the same center. In logistic regression, shorter donor height was associated with secondary discard (odds ratio 0.97 per cm, 95% CI 0.94‐1.00, P= .02). SLT volume by center was not predictive of secondary discard. Current policy proposals that incentivize SLT in the United States could increase the number of transplants to children and adults. In this analysis of deceased donor liver offers in the United States that were ultimately split between 2010‐2014, the authors find that split liver transplants most often benefit a smaller adult (median height of 163cm) and a child, only 61% of adult deceased donor livers split met “optimal” split criteria, and shorter donor height was associated with secondary discard.

Risk scoring for patients with cirrhosis has evolved greatly over the past several decades. However, patients with low Model for End-Stage Liver Disease–Sodium scores still suffer from liver-related morbidity and mortality. Unfortunately, it is not clear which of these low Model for End-Stage Liver Disease–Sodium score patients would benefit from earlier consideration of liver transplantation. This article reviews the literature of risk prediction in patients with cirrhosis, identifies which patients may benefit from earlier interventions, such as transplantation, and proposes directions for future research.

Supplemental Digital Content is available in the text.

The field of liver transplantation has shifted considerably in the MELDera, including changing allocation, immunosuppression, and liver failure etiologies, as well as better supportive therapies. Our aim was to evaluate the predictive accuracy of the MELDscore over time. The United Network for Organ Sharing provided de‐identified data on 120 156 patients listed for liver transplant from 2002‐2016. The ability of the MELDscore to predict 90‐day mortality was evaluated by a concordance (C‐) statistic and corroborated with competing risk analysis. The MELDscore's concordance with 90‐day mortality has downtrended from 0.80 in 2003 to 0.70 in 2015. While lab MELDscores at listing and transplant climbed in that interval, score at waitlist death remained steady near 35. Listing age increased from 50 to 54 years. HCV‐positive status at listing dropped from 33 to 17%. The concordance of MELDand mortality does not differ with age (>60 = 0.73, <60 = 0.74), but is lower in diseases that are increasing most rapidly—alcoholic liver disease and non‐alcoholic fatty liver disease—and higher in those that are declining, particularly in HCV‐positive patients (HCVpositive = 0.77; negative = 0.73). While MELDstill predicts mortality, its accuracy has decreased; changing etiology of disease may contribute. The MELD and its successor, the MELD‐Na, while still reasonable surrogates for acuity of illness in individuals with liver disease, are growing less predictive of waitlist death within 90 days in the modern era, likely due to a combination of changing etiologies of liver disease and an older, sicker patient population. See Mahmud and Goldberg's editorial on page 3221.

The field of liver transplantation has shifted considerably in the MELD era, including changing allocation, immunosuppression, and liver failure etiologies, as well as better supportive therapies. Our aim was to evaluate the predictive accuracy of the MELD score over time. The United Network for Organ Sharing provided de-identified data on 120 156 patients listed for liver transplant from 2002-2016. The ability of the MELD score to predict 90-day mortality was evaluated by a concordance (C-) statistic and corroborated with competing risk analysis. The MELD score’s concordance with 90-day mortality has downtrended from 0.80 in 2003 to 0.70 in 2015. While lab MELD scores at listing and transplant climbed in that interval, score at waitlist death remained steady near 35. Listing age increased from 50 to 54 years. HCV-positive status at listing dropped from 33 to 17%. The concordance of MELD and mortality does not differ with age (>60 = 0.73, <60 = 0.74), but is lower in diseases that are increasing most rapidly—alcoholic liver disease and non-alcoholic fatty liver disease—and higher in those that are declining, particularly in HCV-positive patients (HCV positive = 0.77; negative = 0.73). While MELD still predicts mortality, its accuracy has decreased; changing etiology of disease may contribute.

IMPORTANCE: Among liver transplant candidates, obesity and frailty are associated with increased risk of death while they are on the wait-list. However, use of body mass index (BMI) may not detect candidates at a higher risk of death owing to the fact that ascites and muscle wasting are seen across transplant candidates of all BMI measurements. OBJECTIVE: To evaluate whether the association between wait-list mortality and frailty varied by BMI of liver transplant candidates. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted at 9 liver transplant centers in the United States from March 1, 2012, to May 1, 2018, among 1108 adult liver transplant candidates without hepatocellular carcinoma. EXPOSURES: At outpatient evaluation, the Liver Frailty Index score was calculated (grip strength, chair stands, and balance), with frailty defined as a Liver Frailty Index score of 4.5 or more. Candidates’ BMI was categorized as nonobese (18.5-29.9), class 1 obesity (30.0-34.9), and class 2 or greater obesity (≥35.0). MAIN OUTCOMES AND MEASURES: The risk of wait-list mortality was quantified using competing risks regression by candidate frailty, adjusting for age, sex, race/ethnicity, Model for End-stage Liver Disease Sodium score, cause of liver disease, and ascites, including an interaction with candidate BMI. RESULTS: Of 1108 liver transplant candidates (474 women and 634 men; mean [SD] age, 55 [10] years), 290 (26.2%) were frail; 170 of 670 nonobese candidates (25.4%), 64 of 246 candidates with class 1 obesity (26.0%), and 56 of 192 candidates with class 2 or greater obesity (29.2%) were frail (P = .57). Frail nonobese candidates and frail candidates with class 1 obesity had a higher risk of wait-list mortality compared with their nonfrail counterparts (nonobese candidates: adjusted subhazard ratio, 1.54; 95% CI, 1.02-2.33; P = .04; and candidates with class 1 obesity: adjusted subhazard ratio, 1.72; 95% CI, 0.99-2.99; P = .06; P = .75 for interaction). However, frail candidates with class 2 or greater obesity had a 3.19-fold higher adjusted risk of wait-list mortality compared with nonfrail candidates with class 2 or greater obesity (95% CI, 1.75-5.82; P &lt; .001; P = .047 for interaction). CONCLUSIONS AND RELEVANCE: This study’s finding suggest that among nonobese liver transplant candidates and candidates with class 1 obesity, frailty was associated with a 2-fold higher risk of wait-list mortality. However, the mortality risk associated with frailty differed for candidates with class 2 or greater obesity, with frail candidates having a more than 3-fold higher risk of wait-list mortality compared with nonfrail patients. Frailty assessments may help to identify vulnerable patients, particularly those with a BMI of 35.0 or more, in whom a clinician’s visual evaluation may be less reliable to assess muscle mass and nutritional status.

The article discusses possibility of speech technology as a big wave in computer interfaces. Speech technology is expected to bring the Internet to every one. The article confers to speech-recognition technology, the innovation of computing on the basis of voice properties. This technology transforms an acoustic signal into textual words and makes the user independent from constraints of general interface. The technology continues to improve but does not yet come close to approximating the speech-recognition capacity of an adult human. Although speech technology cannot be used in all situations to replace keyboards, it is already being used productively in a variety of applications and promises pervasive computing. In this regard, VoiceXML, an XML-based markup language supporting voice access of web-based services is under development at IBM Research division. There are issues in this technology, like errors due to variability of the speaker, and the acoustic environment in which the speech is produced. The key to a successful future for conversational systems is using speech effectively and unobtrusively in solutions for users' everyday problems, not just because it's cool technology.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clbgenomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin’s DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention.

Frailty has emerged as a powerful predictor of outcomes in patients with cirrhosis and has inevitably made its way into decision making within liver transplantation. In an effort to harmonize integration of the concept of frailty among transplant centers, the ASTand ASTSsupported the efforts of our working group to develop this statement from experts in the field. Frailty is a multidimensional construct that represents the end‐manifestation of derangements of multiple physiologic systems leading to decreased physiologic reserve and increased vulnerability to health stressors. In hepatology/liver transplantation, investigation of frailty has largely focused on physicalfrailty, which subsumes the concepts of functional performance, functional capacity, and disability. There was consensus that every liver transplant candidate should be assessed at baseline and longitudinally using a standardized frailty tool, which should guide the intensity and type of nutritional and physical therapy in individual liver transplant candidates. The working group agreed that frailty should not be used as the sole criterion for delisting a patient for liver transplantation, but rather should be considered one of many criteria when evaluating transplant candidacy and suitability. A road map to advance frailty in the clinical and research settings of liver transplantation is presented here. This summary statement about frailty in liver transplantation addresses how to define and measure frailty, and how to incorporate frailty into the care of patients with end‐stage liver disease, including those awaiting liver transplantation.

Functional impairment is associated with mortality in adult liver transplant candidates. This has not been studied in pediatric liver transplant candidates. United Network for Organ Sharing Standard Transplant Analysis and Research files were used to investigate functional status, waitlist mortality, and posttransplant outcomes in children younger than 18 years who were waitlisted in 2006-2016 for primary liver transplant. Functional status was categorized, by using the Lansky Play-Performance Scale (LPPS), as normal/good (80-100), moderately impaired (50-70), or severely impaired (10-40) by center assessment. Among 3250 children not listed as Status 1A, 62% had an LPPS score of 80-100, 25% had a score of 50-70, and 13% had a score of 10-40 at listing. Children with an LPPS score of 10-40 at listing were more likely to die while on the waitlist (standardized hazard ratio 1.85, 95% confidence interval 1.09-3.13, P= .02) in analyses adjusting for being on a ventilator, breathing support, or dialysis and other illness severity measures. For the 2565 children transplanted, an LPPS score of 10-40 at listingdrastically increased mortality risk by 1 year posttransplant(hazard ratio 5.77, 95% confidence interval 3.05-10.91, P< .0005). LPPS scores of 10-40 and 50-70 both increased the risk of graft loss by 1 year. Functional status is an independent predictor of waitlist and posttransplant mortality in pediatric liver transplant candidates. Validated tools for the assessment of functional status in these children would improve our ability to predict mortality risk—and to appropriately prioritize them for transplant.

A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.

'OPEN the pod bay doors, HAL.' The HAL9000 computer responsible for the Discovery spacecraft's mission to Jupiter in the classic 1968 movie 2001: A Space Odyssey by Stanley Kubrick and […]