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OBJECTIVE: To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. METHODS: Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0). RESULTS: A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well. CONCLUSION: Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent-onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures. METHODS: Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second-line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG-U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance-weighted discrimination normalization. RESULTS: Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor beta-inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets. CONCLUSION: Gene expression signatures in PBMCs from patients with recent-onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the usefulness of ischemic resting electrocardiogram (ECG), ankle brachial index (ABI) <0.8, ankle brachial difference (ABD) > or = 75 mm Hg (a marker of peripheral medial arterial wall calcification), and estimated glucose disposal rate (eGDR) (a marker for insulin resistance) for predicting mortality risk in the context of standard risk factors.Methods: Data are from participants in the Pittsburgh Epidemiology of Diabetes Complications Study of 658 subjects with childhood onset Type 1 diabetes of mean age 28 years (range 8-48) and duration of diabetes 19 years (range 7-37) at baseline. Deaths were confirmed by death certificates.Results: There were 68 deaths from all causes during 10 years follow-up. In univariate analysis, the mortality hazard ratios and 95% confidence intervals associated with ischemic ECG (6.7, 3.7-12.1), the lowest quintile of eGDR (i.e., the most insulin resistant) (6.7, 4.1-10.9), ABI <0.8 (2.5, 1.1-5.9), and ABD > or = 75 mm Hg (6.7) were only marginally less than those conveyed by pre-existing coronary artery disease (8.4, 4.7-15.2) or overt nephropathy (7.6, 4.5-12.9). Ischemic ECG and eGDR were independent mortality predictors, together with duration of diabetes, coronary artery disease, overt nephropathy, nonhigh density lipoprotein cholesterol, and smoking history. If serum creatinine was available, it entered, and glycosylated hemoglobin replaced eGDR.Conclusions: Estimated GDR and ECG ischemia are strong predictors of mortality in type 1 diabetes and may be useful in the identification of those at risk. [ABSTRACT FROM AUTHOR]

We studied the relationship of coronary artery calcification (CAC), a marker of coronary atherosclerosis, with prevalent clinical coronary artery disease (CAD) and established cardiovascular disease (CVD) risk factors in a type 1 diabetic population. At the 10-year follow-up examination of the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study cohort, 302 adults (mean age 38.1 +/- 7.8 years) received electron beam tomography (EBT) scanning of the heart and a clinical examination. Clinical CAD was defined as a confirmed history of myocardial infarction (MI), angiographic stenosis > or =50%, Pittsburgh EDC Study physician-diagnosed angina, or ischemic electrocardiogram (ECG). CAC correlated with most CVD risk factors. CAC had 84 and 71% sensitivity for clinical CAD in men and women, respectively, and 100% sensitivity for MI or obstructive CAD. A CACS cut point of 400 was the most efficient coronary calcium correlate of CAD. In subjects with angina only, CAC sensitivity was 83% in men and 46% in women. In logistic regression, CAC, ECG R-R variation, peripheral vascular disease, and Beck Depression Inventory independently correlated with prevalent CAD in men and overall. Except for CAC, the same variables independently correlated with CAD in women, and age also entered the model. CAC was an independent correlate of MI or obstructive CAD in both sexes and was the strongest independent correlate in men, but CAC was not independently associated with angina and ischemic ECG in either sex. It is concluded that EBT-detected CAC is strongly correlated with CAD in type 1 diabetes-particularly in men. [ABSTRACT FROM AUTHOR]

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The treatment of choice for hepatorenal syndrome-acute kidney injury (HRS-AKI) is vasoconstrictor therapy in combination with albumin, preferably norepinephrine or terlipressin as recommended by recent guidelines. In the absence of larger head-to-head trials comparing the efficacy of terlipressin and norepinephrine, meta-analysis of smaller studies can provide insights needed to understand the comparative effects of these medications. Additionally, recent changes in the HRS diagnosis and treatment guidelines underscore the need for newer analyses comparing terlipressin and norepinephrine. In this systematic review, we aimed to assess reversal of hepatorenal syndrome (HRS) and 1-month mortality in subjects receiving terlipressin or norepinephrine for the management of HRS-AKI. We searched literature databases, including PubMed, Cochrane, Clinicaltrials.gov, International Clinical Trials Registry Platform, Embase, and ResearchGate, for randomized controlled trials (RCTs) published from January 2007 to June 2023 on June 26, 2023. Only trials comparing norepinephrine and albumin with terlipressin and albumin for the treatment of HRS-AKI in adults were included, and trials without HRS reversal as an endpoint or nonresponders were excluded. Pairwise meta-analyses with the random effects model were conducted to estimate odds ratios (ORs) for HRS reversal and 1-month mortality as primary outcomes. Additional outcomes assessed, included HRS recurrence, predictors of response, and incidence of adverse events (AEs). We used the Cochrane risk of bias assessment tool for quality assessment. We included 7 RCTs with a total of 376 subjects with HRS-AKI or HRS type 1. This meta-analysis showed numerically higher rates of HRS reversal (OR 1.33, 95% confidence interval [CI] [0.80-2.22]; P = 0.22) and short-term survival (OR 1.50, 95% CI [0.64-3.53]; P = 0.26) with terlipressin, though these results did not reach statistical significance. Terlipressin was associated with AEs such as abdominal pain and diarrhea, whereas norepinephrine was associated with cardiovascular AEs such as chest pain and ischemia. Most of the AEs were reversible with a reduction in dose or discontinuation of therapy across both arms. Of the terlipressin-treated subjects, 5.3% discontinued therapy due to serious AEs compared to 2.7% of the norepinephrine-treated subjects. Limitations of this analysis included small sample size and study differences in HRS-AKI diagnostic criteria. As more studies using the new HRS-AKI criteria comparing terlipressin and norepinephrine are completed, a clearer understanding of the comparability of these 2 therapies will emerge., Competing Interests: Both JCO and RMS have served as consultants for Mallinckrodt Pharmaceuticals related to terlipressin. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2024 Olson, Subramanian. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The Sepsis-3 guidelines have incorporated serum lactate levels of >2 mmol/L in septic shock definition to account for higher observed mortality. Further evidence is needed to support this threshold in cirrhosis, as well as target mean arterial pressure (MAP) during resuscitation., Methods: This observational cohort study investigated the association between initial serum lactate and resuscitation MAP levels on in-hospital mortality in patients with and without cirrhosis. Patients admitted to the intensive care unit for the treatment of septic shock between 2006 and 2021 in a quaternary academic center were included. Patients with cirrhosis documented on imaging and International Classification of Disease codes (n=595) were compared to patients without cirrhosis (n=575). The association of intensive care unit admission lactate levels and median 2-hour MAP with in-hospital mortality and the need for continuous renal replacement therapy was assessed. The association between median 24-hour MAP and in-hospital mortality was analyzed post hoc., Results: Within the cirrhosis group, admission lactate levels of 2-4 and >4 mmol/L were associated with increased in-hospital mortality compared to lactate <2 mmol/L [adjusted odds ratio (aOR): 1.69, CI: 1.03-2.81, aOR: 4.02, CI: 2.53-6.52]. Median 24-hour MAP 60-65 and <60 mm Hg were also associated with increased in-hospital mortality compared with MAP >65 mm Hg (aOR: 2.84, CI: 1.64-4.92 and aOR: 7.34, CI: 3.17-18.76). In the noncirrhosis group, associations with in-hospital mortality were weaker for lactate 2-4 and >4 mmol/L (aOR: 1.32, CI: 0.77-2.27 and aOR: 2.25, CI: 1.40-3.67) and median 24-hour MAP 60-65 and <60 mm Hg (aOR: 1.70, CI: 0.65-4.14 and aOR: 4.41, CI: 0.79-29.38)., Conclusions: These findings support utilizing lactate >2 mmol/L in the definition of septic shock, as well as a target MAP of >65 mm Hg during resuscitation in patients with cirrhosis., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Competing Interests: Conflicts of interest were reviewed and adjudicated by the co-chairs and co-vice chairs of the guidelines. In the event an individual disclosed a conflict or potential conflict by submitted form or verbally during the process of guidelines, those individuals abstained from voting on related questions. The taskforce followed all procedures as documented in the American College of Critical Care Medicine/Society of Critical Care Medicine (SCCM) Standard Operating Procedures Manual. Drs. Singbartl, Nanchal, Killian, Olson, Karvellas, Subramanian, and Truwit disclosed authorship on several related articles with potential intellectual conflicts explored and adjudicated. Dr. Dionne described volunteer service for Canadian Association of Gastroenterology, American College of Gastroenterology, American Gastroenterological Association, and European Society of Intensive Care Medicine. Dr. Hyzy described volunteer service for American Thoracic Society, Quality Improvement and Implementation Committee, and the SCCM Finance Committee as well as service as an expert witness in a previous medical case involving this subject matter. Taylor advised of service as an author on the SCCM/American Society for Parenteral and Enteral Nutrition (ASPEN) nutrition guidelines and service on the ASPEN research committee. Dr. Huang disclosed service on the American College of Emergency Physicians sepsis task force. Dr. Karvellas disclosed service on an acute liver failure study group. Dr. Hyzy and Dr. Olson disclosed being expert witnesses. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Objectives: To develop evidence-based recommendations for clinicians caring for adults with acute liver failure (ALF) or acute on chronic liver failure (ACLF) in the ICU., Design: The guideline panel comprised 27 members with expertise in aspects of care of the critically ill patient with liver failure or methodology. We adhered to the Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development., Interventions: In part 2 of this guideline, the panel was divided into four subgroups: neurology, peri-transplant, infectious diseases, and gastrointestinal groups. We developed and selected Population, Intervention, Comparison, and Outcomes (PICO) questions according to importance to patients and practicing clinicians. For each PICO question, we conducted a systematic review and meta-analysis where applicable. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements., Measurements and Main Results: We report 28 recommendations (from 31 PICO questions) on the management ALF and ACLF in the ICU. Overall, five were strong recommendations, 21 were conditional recommendations, two were best-practice statements, and we were unable to issue a recommendation for five questions due to insufficient evidence., Conclusions: Multidisciplinary, international experts formulated evidence-based recommendations for the management ALF and ACLF patients in the ICU, acknowledging that most recommendations were based on low quality and indirect evidence., Competing Interests: Conflicts of interest were reviewed and adjudicated by the co-chairs and co-vice chairs of the guidelines. In the event an individual disclosed a conflict or potential conflict by submitted form or verbally during the process of guidelines, those individuals abstained from voting on related questions. The taskforce followed all procedures as documented in the American College of Critical Care Medicine/Society of Critical Care Medicine (SCCM) Standard Operating Procedures Manual. Drs. Singbartl, Nanchal, Killian, Olson, Karvellas, Subramanian, and Truwit disclosed authorship on several related articles with potential intellectual conflicts explored and adjudicated. Dr. Dionne described volunteer service for Canadian Association of Gastroenterology, American College of Gastroenterology, American Gastroenterological Association, and European Society of Intensive Care Medicine. Dr. Hyzy described volunteer service for American Thoracic Society, Quality Improvement and Implementation Committee, and the SCCM Finance Committee as well as service as an expert witness in a previous medical case involving this subject matter. Dr. Taylor advised of service as an author on the SCCM/American Society of Parenteral and Enteral Nutrition (ASPEN) nutrition guidelines and service on the ASPEN research committee. Dr. Huang disclosed service on the American College of Emergency Physicians Sepsis Task Force. Dr. Karvellas disclosed service on an Acute Liver Failure Study Group. Dr. Hollenberg disclosed that he is a member of American College of Chest Physicians, American Heart Association, and American College of Cardiology. Dr. Olson disclosed that she is a member of American Association for the Study of Liver Disease. Dr. Steadman disclosed that he is a co-author on “Management of the Critically Ill Patient with Cirrhosis: A Multidisciplinary Perspective.” J Hepatology 2015 pending publication, and that he is currently writing guidelines for Anesthesiology Transplant fellowship for the International Liver Transplant Society. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine.)

This study assessed the potential advantages of treating hepatorenal syndrome-acute kidney injury (HRS-AKI) with terlipressin versus placebo in the ICU setting., Design: Patients were randomly assigned in a 2:1 ratio to receive terlipressin or placebo for up to 14 days., Setting: A retrospective analysis of data from the phase III CONFIRM study., Participants: Adult patients with HRS-AKI admitted to the ICU., Main Outcomes and Measures: In this substudy, we evaluated outcomes of the ICU stay and the need for organ support, including renal replacement therapy (RRT)., Results: Among 300 patients with HRS-AKI from the CONFIRM study, 45 were treated in the ICU (terlipressin, 31/199 [16%]; placebo, 14/101 [14%]). On ICU admission, baseline demographics were similar across treatment arms, including severity of liver dysfunction. Among patients alive at the end of the ICU stay, those randomized to terlipressin had a significantly shorter median length of ICU stay than placebo (4 vs 11 d; p < 0.001). Terlipressin-treated patients had a significantly larger improvement in renal function from baseline versus placebo (-0.7 vs +0.2 mg/dL; p = 0.001), including when accounting for the interaction between treatment and day-of-patient-admission to the ICU (-0.7 vs +0.9 mg/dL; p < 0.001). Cumulative requirement for RRT through day 90 was improved in the terlipressin arm versus placebo (10/31 [32%] vs 8/14 [57%]; p = 0.12), although not significantly. Of 13 patients who received a liver transplant, five out of five (100%) in the placebo arm needed RRT through day 90 versus five out of eight (63%) in the terlipressin arm., Conclusions: In this subanalysis of CONFIRM, patients admitted to the ICU with HRS-AKI who received terlipressin were more likely to achieve renal function improvement, based on serum creatinine changes by the end of treatment, and had significantly shorter lengths of ICU stay than patients randomized to the placebo arm., Competing Interests: Drs. Subramanian and Olson received consultancy fees from Mallinckrodt Pharmaceuticals. Dr. Jamil is an employee of Mallinckrodt Pharmaceuticals. Dr. Karvellas has disclosed that he does not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Purpose of Review: Liver transplantation remains the only definitive treatment for advanced liver disease and liver failure. Current allocation schemes utilized for liver transplantation mandate a 'sickest first' approach, thus most liver transplants occur in patients with severe systemic illness. For intensive care providers who care for liver transplant recipients, a foundation of knowledge of technical considerations of orthotopic liver transplantation, basic management considerations, and common complications is essential. This review highlights the authors' approach to intensive care management of the postoperative liver transplant recipient with a review of common issues, which arise in this patient population., Recent Findings: The number of centers offering liver transplantation continues to increase globally and the number of patients receiving liver transplantation also continues to increase. The number of patients with advanced liver disease far outpaces organ availability and, therefore, patients undergoing liver transplant are sicker at the time of transplant. Outcomes for liver transplant patients continue to improve owing to advancements in surgical technique, immunosuppression management, and intensive care management of liver disease both pretransplant and posttransplant., Summary: Given a global increase in liver transplantation, an increasing number of intensive care professionals are likely to care for this patient population. For these providers, a foundational knowledge of the common complications and key management considerations is essential., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a serious complication of severe liver disease with a clinically poor prognosis. Supportive care using vasoconstrictors and intravenous albumin are the current mainstays of therapy. Terlipressin is an efficacious vasoconstrictor that has been used for 2 decades as the first-line treatment for HRS-AKI in Europe and has demonstrated greater efficacy in improving renal function compared to placebo and other vasoconstrictors. One of the challenges associated with terlipressin use is monitoring and mitigating serious adverse events, specifically adverse respiratory events, which were noted in a subset of patients in the recently published CONFIRM trial, the largest randomized trial examining terlipressin use for HRS-AKI. In this article, we review terlipressin's pharmacology, hypothesize how its mechanism contributes to the risk of respiratory compromise and propose strategies that will decrease the frequency of these events by rationally selecting patients at lower risk for these events., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Acute liver failure (ALF) is an orphan disease often complicated by acute kidney injury (AKI). We assessed the impact of transient versus persistent AKI on survival in patients with ALF., Design: International multicenter retrospective cohort., Setting: U.S. ALF Study Group prospective registry., Patients: Patients with greater than or equal to 18 years and ALF in the registry from 1998 to 2016 were included. Patients with less than 3 days of follow-up, without kidney function evaluation on day 3, or with cirrhosis were excluded., Interventions: AKI was defined by Kidney Disease Improving Global Outcomes guidelines on day 1. Kidney recovery was defined on day 3 as transient AKI, by a return to no-AKI within 48 hours or persistent AKI if no such recovery or renal replacement therapy (RRT) was observed. Primary outcome was transplant-free survival (TFS) at 21 days., Measurements and Main Results: Among 1,071 patients with ALF, 339 (31.7%) were males, and median (interquartile range) age was 39 years (29-51 yr). Acetaminophen-related ALF was found in 497 patients (46.4%). On day 1, 485 of 1,071 patients (45.3%) had grade 3-4 hepatic encephalopathy (HE), 500 of 1,070 (46.7%) required invasive mechanical ventilation (IMV), 197 of 1,070 (18.4%) were on vasopressors, and 221 of 1,071 (20.6%) received RRT. On day 1, 673 of 1,071 patients (62.8%) had AKI. On day 3, 72 of 1,071 patients (6.7%) had transient AKI, 601 of 1,071 (56.1%) had persistent AKI, 71 of 1,071 (6.6%) had late onset AKI, and 327 of 1,071 (30.5%) remained without AKI. Following adjustment for confounders (age, sex, race, etiology, HE grade, use of IMV and vasopressors, international normalized ratio, and year), although persistent acute kidney injury (adjusted odds ratio [aOR] [95% CI] 0.62 [0.44-0.88]) or late onset AKI (aOR [95% CI] 0.48 [0.26-0.89]) was associated with lower TFS, transient AKI was not (aOR [95% CI] 1.89 [0.99-3.64])., Conclusions: In a multicenter cohort of patients with ALF, persistent but not transient AKI was independently associated with lower short-term TFS., Competing Interests: Drs. Cardoso, Lee, and Karvellas received support for article research from the National Institutes of Health. Dr. Bagshaw received funding from Baxter and BioPorto. Dr. Olson received funding from Mallinckrodt Pharmaceuticals. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Purpose of Review: Intensive care management of patients who have undergone organ transplantation of liver, small bowel, pancreas, and/or kidney requires a basic knowledge of immunosuppression principles and the management of immunosuppressive medications. This review highlights the core principles of immunosuppression management in abdominal organ transplantation with a focus on complications arising from immunosuppressive drugs, both in the immediate postoperative period and in long-term usage., Recent Findings: The general principles of management of immunosuppression in the abdominal organ transplant population have remained largely unchanged. Improvements in drug monitoring coupled with improvements in knowledge of pathways involved in allograft rejection have further refined immunosuppressive therapy. Infectious and central nervous system complications remain prevalent and are common complications of immunosuppressive drug therapy., Summary: For the intensive care professional who cares for abdominal organ transplant recipients, a foundational knowledge of the core principles of immunosuppression management is essential. In addition, an understanding of the common immunosuppressive drug regimens and the complications associated with these regimens is required for optimal management, risk assessment, and outcomes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The molecular adsorbent recirculating system removes water-soluble and albumin-bound toxins and may be beneficial for acute liver failure patients. We compared the rates of 21-day transplant-free survival in acute liver failure patients receiving molecular adsorbent recirculating system therapy and patients receiving standard medical therapy., Design: Propensity score-matched retrospective cohort analysis., Setting: Tertiary North American liver transplant centers., Patients: Acute liver failure patients receiving molecular adsorbent recirculating system at three transplantation centers (n = 104; January 2009-2019) and controls from the U.S. Acute Liver Failure Study Group registry., Interventions: Molecular adsorbent recirculating system treatment versus standard medical therapy (control)., Measurements and Main Results: One-hundred four molecular adsorbent recirculating system patients were propensity score-matched (4:1) to 416 controls. Using multivariable conditional logistic regression adjusting for acute liver failure etiology (acetaminophen: n = 248; vs nonacetaminophen: n = 272), age, vasopressor support, international normalized ratio, King's College Criteria, and propensity score (main model), molecular adsorbent recirculating system was significantly associated with increased 21-day transplant-free survival (odds ratio, 1.90; 95% CI, 1.07-3.39; p = 0.030). This association remained significant in several sensitivity analyses, including adjustment for acute liver failure etiology and propensity score alone ("model 2"; molecular adsorbent recirculating system odds ratio, 1.86; 95% CI, 1.05-3.31; p = 0.033), and further adjustment of the "main model" for mechanical ventilation, and grade 3/4 hepatic encephalopathy ("model 3"; molecular adsorbent recirculating system odds ratio, 1.91; 95% CI, 1.07-3.41; p = 0.029). In acetaminophen-acute liver failure (n = 51), molecular adsorbent recirculating system was associated with significant improvements (post vs pre) in mean arterial pressure (92.0 vs 78.0 mm Hg), creatinine (77.0 vs 128.2 µmol/L), lactate (2.3 vs 4.3 mmol/L), and ammonia (98.0 vs 136.0 µmol/L; p ≤ 0.002 for all). In nonacetaminophen acute liver failure (n = 53), molecular adsorbent recirculating system was associated with significant improvements in bilirubin (205.2 vs 251.4 µmol/L), creatinine (83.1 vs 133.5 µmol/L), and ammonia (111.5 vs 140.0 µmol/L; p ≤ 0.022 for all)., Conclusions: Treatment with molecular adsorbent recirculating system is associated with increased 21-day transplant-free survival in acute liver failure and improves biochemical variables and hemodynamics, particularly in acetaminophen-acute liver failure., Competing Interests: Dr. Durkalski-Maudlin’s institution received funding from the National Institutes of Health (NIH) and the National Institute of Diabetes and Digestive and Kidney Diseases. Drs. Durkalski-Maudlin and Karvellas received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Critically ill cirrhotic patients are increasingly transplanted, but there is no consensus about futile liver transplantation (LT). Therefore, the decision to delay or deny LT is often extensively debated. These debates arise from different opinions of futility among transplant team members. This study aims to achieve a multinational and multidisciplinary consensus on the definition of futility in LT and to develop well-articulated criteria for not proceeding with LT due to futility., Methods: Thirty-five international experts from anesthesiology/intensive care, hepatology, and transplant surgery were surveyed using the Delphi method. More than 70% of similar answers to a question were necessary to define agreement., Results: The panel recommended patient and graft survival at 1 year after LT to define futility. Severe frailty and persistent fever or <72 hours of appropriate antimicrobial therapy in case of ongoing sepsis were considered reasons to delay LT. A simple assessment of the number of organs failing was considered the most appropriate way to decide whether LT should be delayed or denied, with respiratory, circulatory and metabolic failures having the most influence in this decision. The thresholds of severity of organ failures contraindicating LT for which a consensus was achieved were a Pao2/FiO2 ratio<150 mm Hg, a norepinephrine dose >1 μg/kg per minute and a serum lactate level >9 mmol/L., Conclusions: Our expert panel provides a consensus on the definition of futile LT and on specific criteria for postponing or denying LT. A framework that may facilitate the decision if a patient is too sick for transplant is presented., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To measure age-related changes in thoracic vertebral body heights (VBH) in skeletally immature normative and scoliotic rabbits to assess how VBH change during growth. To examine the potential link between the moment-arm of the rib tether and vertebral wedging as well as the sum of the curvature angles at the apical level (T7). To assess the correlation between the magnitude of initial spine curve and final spine curve in the scoliotic group., Methods: Eight healthy, skeletally immature normative New Zealand rabbits and ten skeletally immature scoliotic rabbits which underwent unilateral rib tethering were included retrospectively. Each rabbit was scanned at two to four time points (at 7, 11, 14 and 28 weeks). Three dimensional bone models of thoracic vertebrae (T1-T12) were digitally segmented and reconstructed. VBH were calculated using surface landmark points from each thoracic vertebra. Apical level (T7) ± 2 levels in scoliotic rabbits were compared to their corresponding levels and time points in the normative group. The moment-arms between the centroids of 2D projections of T3-T9 vertebral bodies and the line which connects the centroids of the end levels were calculated., Results: Bilateral left-right (L-R) symmetry and anterior-posterior (A-P) asymmetry were observed in normative VBH. Bilateral concave-convex (CC-CX) asymmetry and (A-P) asymmetry were observed in scoliotic VBH. No significant differences in growth rates were found between the normative and scoliotic groups. Vertebral wedging as well as curvature magnitude were positively correlated with the moment-arms., Conclusion: Unilateral rib tether applies compressive forces on both concave and convex sides, whereas compressive forces are lower on the latter. Knowing the amount of vertebral wedging or curve magnitude would enable us to predict the applied force (moment-arms), which is important for planning a corrective surgery., Competing Interests: The authors declare no potential conflict of interest., (© 2020 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Purpose of Review: ICU admissions due to complications of advanced liver disease continue to rise. Among indications for admission to the ICU in patients with cirrhosis, gastrointestinal issues such as bleeding are common. In patients in whom gastrointestinal issues are not the principal indication for ICU, gastrointestinal issues such as nutrition and ileus remain important concerns for generalized intensive care support. This review highlights current trends in management of gastrointestinal issues in patients with cirrhosis admitted to the ICU., Recent Findings: General management of upper gastrointestinal bleeding remains largely unchanged. Improvements in interventional techniques have increased the options for difficult to control bleeding, these include the development of expandable esophageal stents and expanded experience with advanced interventional radiology techniques for the management of bleeding gastric varices. Frailty as an important prognostic marker in advanced liver disease and liver transplantation is the subject of several new studies and serves to highlight the importance of nutrition in the management of the critically ill cirrhotic patient., Summary: Gastrointestinal complications are frequent in the critically ill cirrhotic patient. Recognition and intervention in a timely manner may minimize morbidity and mortality and result in improved outcomes for this vulnerable population.

Introduction: This study aimed to evaluate the factors that influence potential orthodontic patients choosing an orthodontist, general dentist, or direct-to-consumer (DTC) aligners for their treatment, and to determine the level of interest in each provider type., Methods: An electronic survey was administered to 249 adults among the general population in the United States to determine and evaluate the level of interest in pursuing orthodontic treatment with each provider type., Results: When asked their preference for provider type, 44% of respondents selected orthodontist, 34% selected DTC aligners, and 22% selected general dentist. Among respondents with the highest level of interest in pursuing orthodontic treatment, 50% selected orthodontist, and 27% selected DTC aligners (P = 0.002). For respondents with a moderate interest in pursuing treatment, only 21% selected orthodontist, and 48% selected DTC aligners (P = 0.002). The biggest perceived advantage of treatment with orthodontists was the quality of treatment, and for DTC aligners, it was convenience, followed by cost. Among adults with children, 34% selected DTC aligners for themselves, and only 16% selected DTC aligners when selecting for their children (P = 0.0001)., Conclusions: There is a high level of interest among adults in pursuing treatment with both orthodontists and DTC aligners. Patients with the highest level of interest in pursuing orthodontic care tend to prefer orthodontists, whereas those with a moderate interest in pursuing treatment prefer DTC aligners. Patients tend to select orthodontists primarily because of treatment quality, whereas they select DTC aligners for convenience and then cost. Parents tend to select an orthodontist for their child's treatment, even when selecting DTC aligners for themselves., (Copyright © 2019 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Geographic isolation is an important yet underappreciated factor affecting marine reserve performance. Isolation, in combination with other factors, may preclude recruit subsidies, thus slowing recovery when base populations are small and causing a mismatch between performance and stakeholder expectations. Mona Island is a small, oceanic island located within a partial biogeographic barrier-44 km from the Puerto Rico shelf. We investigated if Mona Island's no-take zone (MNTZ), the largest in the U.S. Caribbean, was successful in increasing mean size and density of a suite of snapper and grouper species 14 years after designation. The La Parguera Natural Reserve (LPNR) was chosen for evaluation of temporal trends at a fished location. Despite indications of fishing within the no-take area, a reserve effect at Mona Island was evidenced from increasing mean sizes and densities of some taxa and mean total density 36% greater relative to 2005. However, the largest predatory species remained rare at Mona, preventing meaningful analysis of population trends. In the LPNR, most commercial species (e.g., Lutjanus synagris, Lutjanus apodus, Lutjanus mahogoni) did not change significantly in biomass or abundance, but some (Ocyurus chrysurus, Lachnolaimus maximus), increased in abundance owing to strong recent recruitment. This study documents slow recovery in the MNTZ that is limited to smaller sized species, highlighting both the need for better compliance and the substantial recovery time required by commercially valuable, coral reef fishes in isolated marine reserves., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: Evaluation of patients with acute liver injury (ALI) or acute liver failure (ALF) often includes measurement of plasma levels of acetaminophen, to determine exposure and/or toxicity. However, once liver injury has developed, acetaminophen might be undetectable in plasma. We investigated the association between level of acetaminophen measured and outcomes of patients designated as having ALF or ALI due to acetaminophen toxicity., Methods: We performed a retrospective analysis of data from 434 subjects in the Acute Liver Failure Study Group who met criteria for ALF (coagulopathy and hepatic encephalopathy within 26 weeks of the first symptoms, without pre-existing liver disease) or ALI (severe liver injury with coagulopathy but no encephalopathy) due to acetaminophen toxicity from January 1, 2010 through December 31, 2014. We collected data on patient demographics, biochemical features, reported acetaminophen use, N-acetylcysteine therapy, liver transplant, and outcomes. Descriptive statistics were used to assess patient demographics, clinical characteristics, and outcomes whereas differences in continuous variables between patients with vs without acetaminophen detection on admission were analyzed using the Wilcoxon rank-sum test. The primary aim was to determine the proportion of patients with detectable plasma levels of acetaminophen., Results: Acetaminophen was undetectable in serum samples from 227 patients (52%). There were no significant differences between groups of patients with detectable vs undetectable levels in demographic features, alcohol use, median levels of alanine aspartate, or use of N-acetylcysteine (given to 94.7% of patients with detectable acetaminophen vs 95.9% of those with undetectable acetaminophen; P=.63). We observed a significant difference in median dose taken between patients with detectable (29,500 mg; interquartile range, 15,000 mg-50,007 mg) vs no detectable parent compound (14,950 mg; interquartile range, 3960 mg-25,000) (P=.003). A lower proportion of patients with detectable plasma levels of acetaminophen (72.3%) survived without a liver transplant than of patients with undetectable levels (86.3%) in univariate analysis (P=.0006), although this was not significant in multivariable analysis (P=.12). Although most patients had unintentional overdoses, a higher proportion of patients with suicidal overdoses (43%) had detectable levels of acetaminophen than patients with accidental overdoses (29.3%; P=.01)., Conclusion: More than half of patients who present at the hospital with acetaminophen-induced ALI or ALF have undetectable levels of acetaminophen. Clinicians should not exclude acetaminophen toxicity because of undetectable levels or withhold N-acetylcysteine for patients with ALI or ALF when acetaminophen toxicity is suspected., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the improvement in lung donation and immediate lung function after the implementation of a 360° rotational positioning protocol within an organ procurement organization in the Midwest., Design: Retrospective observational study., Setting: The Midwest Transplant Network from 2005 to 2017. Rotational positioning of donors began in 2008., Subjects: Potential deceased lung donors., Interventions: A 360° rotational protocol. Presence of immediate lung function in recipients, change in PaO2:FIO2 ratio during donor management, initial and final PaO2:FIO2 ratio, and proportion of lungs donated were measured. Outcomes were compared between rotated and nonrotated donors., Measurements and Main Results: A total of 693 donors were analyzed. The proportion of lung donations increased by 10%. The difference between initial PaO2:FIO2 ratio and final PaO2:FIO2 ratio was significantly different between rotated and nonrotated donors (36 ± 116 vs 104 ± 148; p < 0.001). Lungs transplanted from rotated donors had better immediate function than those from nonrotated donors (99.5% vs 68%; p < 0.001)., Conclusions: There was a statistically significant increase in lung donations after implementing rotational positioning of deceased donors. Rotational positioning significantly increased the average difference in PaO2:FIO2 ratios. There was also superior lung function in the rotated group. The authors recommend that organ procurement organizations consider adopting a rotational positioning protocol for donors to increase the lungs available for transplantation.

Purpose of Review: Hospitalizations due to complications of cirrhosis continue to rise. Patients with chronic liver disease who suffer acute decompensation [acute-on-chronic liver failure (ACLF)] often require intensive care support and are at high risk for short-term mortality. Given the high mortality rate associated with this condition is incumbent on intensive care providers who care for this patient population to have a working knowledge of ACLF with its associated complications, management strategies and prognosis., Recent Findings: Recognizing ACLF as a distinct clinical entity has gained international attention in recent years though a consensus does not exist. There has been progress on better defining this clinical entity and recent studies have begun to address the critical care needs of these patients. Additional studies are required to define the best care practices for patients with ACLF., Summary: ACLF is a condition occurring in patients with chronic liver disease which is commonly associated with a need for intensive care support and carries a high risk of short-term mortality. Intensive care specialists must be familiar with diagnosis and management of this condition.

Background: Patients with decompensated hepatitis C virus (HCV) cirrhosis experience various outcomes after sustained virological response (SVR), ranging from clinical recovery to further deterioration. We hypothesised that the genetic risk for steatosis, namely the polymorphisms rs738409 of Patatin-like Phospholipase Domain-Containing 3 ( PNPLA3 ), rs58542926 of Transmembrane-6-Superfamily-2 ( TM6SF2 ), and rs641738 of Membrane-bound O-acyltransferase Domain-Containing 7 ( MBOAT7 ), is predictive of recovery., Methods: We prospectively enrolled 56 patients with Child-Pugh (CPT) B/C cirrhosis who underwent antiviral therapy. The primary outcome was change in CPT score at 12, 24, and 48 weeks after SVR. We used a linear mixed-effects model for analysis., Results: Forty-five patients ( PNPLA3 : 21 CC, 19 CG, 5 GG) survived to the first endpoint without liver transplantation. The mean change in CPT score at 12, 24, and 48 weeks was -1.57 (SE=0.30), -1.76 (SE=0.32), and -2.0 (SE=0.36), respectively, among the patients with the PNPLA3 CC genotype and -0.50 (SE=0.20), -0.41 (SE=0.25), and -0.24 (SE=0.27), respectively, among the other 24 patients. After adjustment for baseline characteristics, the PNPLA3 CG/GG genotypes were associated with a 1.29 (SE=0.30, p<0.0001) point higher CPT score. Most of the difference came from differences in hepatic encephalopathy and bilirubin. The results for rs58542926 and rs641738 were not significant., Conclusion: The PNPLA3 CG/GG genotypes could identify a subgroup of patients with decompensated HCV cirrhosis that had suboptimal clinical recovery despite SVR. An understanding of the genetic factors that influence clinical outcomes will help target patients for liver transplant based on individual genetic risk factors and provide insight leading to new therapeutic approaches., Competing Interests: Competing interests: WD reports speaking and consultation fees from Gilead and Merck. RT reports speaking fees from Bristol-Myers Squibb, Gilead, Intercept, Merck and Salix/Valeant, and consultation fees from Bayer and Gilead. PKP reports speaking fees from AbbVie and Gilead.

Objective: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA)., Methods: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal., Results: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36)., Conclusion: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare., (© 2018, American College of Rheumatology.)

Objective: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease., Methods: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare., Results: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05)., Conclusion: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified., (© 2018, American College of Rheumatology.)

Here we provide reflections of and a tribute to John M. Olson, a pioneering researcher in photosynthesis. We trace his career, which began at Wesleyan University and the University of Pennsylvania, and continued at Utrech in The Netherlands, Brookhaven National Laboratory, and Odense University in Denmark. He was the world expert on pigment organization in the green photosynthetic bacteria, and discovered and characterized the first chlorophyll-containing protein, which has come to be known as the Fenna-Matthews-Olson (FMO) protein. He also thought and wrote extensively on the origin and early evolution of photosynthesis. We include personal comments from Brian Matthews, Raymond Cox, Paolo Gerola, Beverly Pierson and Jon Olson.

Study Design: In a treatment-control animal study expansion thoracoplasty (ET) was performed in a juvenile rabbit model of thoracic insufficiency syndrome (TIS) and benefits to thoracic development and respiratory function quantified. Rabbits treated early versus late were compared to age-matched normal and disease control rabbits through to skeletal maturity., Objective: Evaluate (1) how ET changes the natural TIS disease trajectory and (2) how timing of ET affects changes in spine growth, lung growth, and respiratory mechanics., Summary of Background Data: Pulmonary growth potential is thought to diminish with age; thus, early therapeutic intervention may increase pulmonary growth in children with TIS. However, no direct empirical evidence exists to support this treatment paradigm., Methods: Convex left scoliosis and resultant TIS was induced in 3-week-old rabbits via surgical rib tethering. We compare the efficacy of ET performed at 7 weeks and expanded at 11 weeks (early, n = 7) versus only at 11 weeks of age (late, n = 7) in preserving lung growth and respiratory function relative to normal (n = 8) and disease (n = 10) rabbits. Sequential computed tomography images and pulmonary function testing was performed to quantify spine curvature, lung growth, and respiratory volumes. At 28 weeks of age chest wall elastance was measured in vivo then acinar complexity analyzed histologically via radial alveolar counts., Results: ET performed early or late altered the predicted trajectory of spine deformity, pulmonary growth inhibition, and respiratory dysfunction seen in disease rabbits. Growth was not significantly different between early and late rabbits and post-treatment gains remained below those of age-matched normal rabbits. Chest wall elastance was impaired by ET and more so in early rabbits, there were no differences in pulmonary elastance., Conclusion: ET interrupted the natural progression of deformity and pulmonary hypoplasia associated with spine curvature in disease rabbits. However, growth benefits are only seen in cases of the most severe initial deformity and must be balanced against the further impairment to chest wall function associated with repetitive surgery., Level of Evidence: N/A.

Purpose of Review: Cirrhosis is a major worldwide health problem which results in a high level of morbidity and mortality. Patients with cirrhosis who require intensive care support have high mortality rates of near 50%. The goal of this review is to address the management of common complications of cirrhosis in the ICU., Recent Findings: Recent epidemiological studies have shown an increase in hospitalizations due to advanced liver disease with an associated increase in intensive care utilization. Given an increasing burden on the healthcare system, it is imperative that we strive to improve our management cirrhotic patients in the intensive care unit. Large studies evaluating the management of patients in the intensive care setting are lacking. To date, most recommendations are based on extrapolation of data from studies in cirrhosis outside of the ICU or by applying general critical care principles which may or may not be appropriate for the critically ill cirrhotic patient. Future research is required to answer important management questions.

Objective: The nuclear oncoprotein DEK is an autoantigen associated with juvenile idiopathic arthritis (JIA), especially the oligoarticular subtype. DEK is a secreted chemotactic factor. Abundant levels of DEK and DEK autoantibodies are found in inflamed synovium in JIA. We undertook this study to further characterize the nature of DEK autoantibodies in screening serum samples from 2 different cohorts that consisted mostly of patients with JIA., Methods: DEK autoantibody levels were analyzed in sera from 33 JIA patients, 13 patients with other inflammatory conditions, and 11 healthy controls, as well as in 89 serum samples from JIA patients receiving anti-tumor necrosis factor (anti-TNF) therapy. Recombinant His-tagged full-length DEK protein (1-375 amino acids [aa]) and the 187-375-aa and 1-350-aa His-tagged DEK fragments made in a baculovirus system were used for enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The C-terminal 25-aa fragment of DEK was expressed in a glutathione S-transferase-tagged vector. ELISA results were calculated as area under the curve by the trapezoidal rule., Results: DEK autoantibody levels were significantly higher in patients with polyarticular JIA than in those with oligoarticular JIA, and were higher in patients with polyarticular JIA who had more active disease after cessation of anti-TNF therapy. Immunoblotting against the C-terminal 25-aa fragment of DEK confirmed that this section of the DEK molecule is the most immunogenic domain., Conclusion: DEK autoantibody levels are higher in patients with polyarticular JIA than in those with oligoarticular JIA, and higher in patients who have disease flares after cessation of anti-TNF therapy. The C-terminal 25-aa fragment is the most immunogenic portion of DEK. These findings are significant with respect to the nature of DEK autoantibodies, their contribution to JIA pathogenesis, and their implications for JIA management., (© 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Hyperammonemia has been associated with intracranial hypertension and mortality in patients with acute liver failure (ALF). We evaluated the effect of renal replacement therapy (RRT) on serum ammonia level and outcomes in ALF. This was a multicenter cohort study of consecutive ALF patients from the United States ALF Study Group registry between January 1998 and December 2016. First, we studied the association of ammonia with hepatic encephalopathy (HE) and 21-day transplant-free survival (TFS; n = 1,186). Second, we studied the effect of RRT on ammonia for the first 3 days post study admission (n = 340) and on 21-day TFS (n = 1,186). Higher admission (n = 1,186) median ammonia level was associated with grade 3-4 HE (116 vs. 83 μmol/L) and mortality at day 21 attributed to neurological (181 vs. 90 μmol/L) and all causes (114 vs. 83 μmol/L; P < 0.001 for all). Among 340 patients with serial ammonia levels, 61 (18%) were on continuous RRT (CRRT), 59 (17%) were on intermittent RRT (IRRT), and 220 (65%) received no RRT for the first 2 days. From days 1 to 3, median ammonia decreased by 38%, 23%, and 19% with CRRT, IRRT, and no RRT, respectively. Comparing to no RRT use, whereas ammonia reduction with CRRT was significant (P = 0.007), with IRRT it was not (P = 0.75). After adjusting for year of enrollment, age, etiology, and disease severity, whereas CRRT (odds ratio [OR], 0.47 [95% confidence interval {CI}, 0.26-0.82]) was associated with reduction in 21-day transplant-free all-cause mortality, IRRT (OR, 1.68 [95% CI, 1.04-2.72]) was associated with an increase. Conclusion: In a large cohort of ALF patients, hyperammonemia was associated with high-grade HE and worse 21-day TFS. CRRT was associated with a reduction in serum ammonia level and improvement of 21-day TFS. (Hepatology 2018;67:711-720)., (© 2017 by the American Association for the Study of Liver Diseases.)

Objective: The current Juvenile Idiopathic Arthritis (JIA) Core Set was developed in 1997 to identify the outcome measures to be used in JIA clinical trials using statistical and consensus-based techniques, but without patient involvement. The importance of patient/parent input into the research process has increasingly been recognized over the years. An Outcome Measures in Rheumatology (OMERACT) JIA Core Set Working Group was formed to determine whether the outcome domains of the current core set are relevant to those involved or whether the core set domains should be revised., Methods: Twenty-four people from the United States, Canada, Australia, and Europe, including patient partners, formed the working group. Guided by the OMERACT Filter 2.0 process, we performed (1) a systematic literature review of outcome domains, (2) a Web-based survey (142 patients, 343 parents), (3) an idea-generation study (120 parents), (4) 4 online discussion boards (24 patients, 20 parents), and (5) a Special Interest Group (SIG) activity at the OMERACT 13 (2016) meeting., Results: A MEDLINE search of outcome domains used in studies of JIA yielded 5956 citations, of which 729 citations underwent full-text review, and identified additional domains to those included in the current JIA Core Set. Qualitative studies on the effect of JIA identified multiple additional domains, including pain and participation. Twenty-one participants in the SIG achieved consensus on the need to revise the entire JIA Core Set., Conclusion: The results of qualitative studies and literature review support the need to expand the JIA Core Set, considering, among other things, additional patient/parent-centered outcomes, clinical data, and imaging data.

Purpose of Review: Hepatorenal syndrome (HRS) does not represent the predominant phenotype of acute kidney injury (AKI) in cirrhosis. Early recognition of HRS helps initiate appropriate therapy. The aims of this review are to present redefinition of AKI, to list new biomarkers, to report recent data on vasopressors in HRS and to propose criteria for simultaneous liver and kidney transplantation (SLKT)., Recent Findings: Urine output, which was not part of the definition of AKI might be reconsidered as it has an independent prognostic value. Biomarkers (NGAL and IL-18) could help identify ATN. However, cut-off values have to be clarified. Vasopressors with albumin represent first option in HRS. Continuous infusion of terlipressin has a better safety profile than intravenous boluses. SLKT should be considered whenever native kidney recovery is unlikely [i.e. prolonged renal replacement therapy (RRT) and/or GFR less than 25 ml/min for 6 weeks prior to transplantation]., Summary: New definitions and recent biomarkers may help differentiate HRS from ATN at an earlier stage. Urine output should be reconsidered in the definitions. Even in patients who are not candidates for transplantation, a short trial of RRT is justified whenever needed. SLKT should be considered whenever posttransplant renal recovery is unlikely.

Alcoholic liver disease encompasses the progressive stages of liver dysfunction that culminates in alcoholic cirrhosis (AC) and in severe cases alcoholic hepatitis (AH). Currently, prognostic scores have limited specificity and sensitivity. Plasma keratin-18 (K18) levels are elevated during liver disease and may be biomarkers of outcome. The objective of this study was to determine if total K18 (M65) or caspase-cleaved K18 (M30) levels were different between AC and AH patients. M65 and M30 levels were measured in the plasma of consented healthy controls and patients with AC and AH. Cell death was assessed by TUNEL staining and caspase activity. M65 and M30 values were significantly higher in AC patients compared to healthy controls and further increased in AH patients. The M65 values and the M30/M65 ratios of nonsurviving AH patients were significantly elevated above their surviving counterparts and healthy controls. Statistical analysis indicated that M30/M65 ratios outperformed current indices for accurately distinguishing the prognosis of AH patients. These scores occurred with minimal increase in plasma cell death markers such as ALT and AST. Serum caspase activity, TUNEL staining, and M30 immunohistochemistry in biopsies indicated that serum and tissue values may not correlate well with overall cell death. In conclusion, both M65 and M30 differentiate AH from AC patients, and M65 values and the M30/M65 ratio are capable of predicting early stage mortality; however, they may not accurately reflect pure hepatocyte cell death in these populations, as they do not strongly correlate with traditional cell death markers.

Patients with cirrhosis who are awaiting liver transplantation (LT) are at high risk for developing critical illnesses. Current liver allocation policies that dictate a "sickest first" approach coupled with a mismatch between need and availability of organs result in longer wait times, and thus, patients are becoming increasingly ill while awaiting organ transplantation. Even patients with well-compensated cirrhosis may suffer acute deterioration; the syndrome of acute-on-chronic liver failure (ACLF) results in multisystem organ dysfunction and a marked increase in associated short-term morbidity and mortality. For patients on transplant waiting lists, the development of multisystem organ failure may eliminate candidacy for transplant by virtue of being "too sick" to safely undergo transplantation surgery. The goals of intensive care management of patients suffering ACLF are to rapidly recognize and treat inciting events (eg, infection and bleeding) and to aggressively support failing organ systems to ensure that patients may successfully undergo LT. Management of the critically ill ACLF patient awaiting transplantation is best accomplished by multidisciplinary teams with expertise in critical care and transplant medicine. Such teams are well suited to address the needs of this unique patient population and to identify patients who may be too ill to proceed to transplantation surgery. The focus of this review is to identify the common complications of ACLF and to describe our approach management in critically ill patients awaiting LT in our centers. Liver Transplantation 23 1465-1476 2017 AASLD., (© 2017 by the American Association for the Study of Liver Diseases.)

Background & Aims: Hypoxic hepatitis is a clinical condition precipitated by prolonged periods of oxygen deprivation to the liver. It can have several underlying causes. Despite its prevalence in critically ill patients, which can reach upwards of 10%, very little is known about the mechanisms of injury. Thus, we set out to measure previously identified circulating biomarkers in an attempt to describe mechanisms of injury following hypoxic hepatitis., Methods: Plasma from patients diagnosed with hypoxic hepatitis was collected for this study. Biomarkers of hepatocellular injury, mitochondrial damage and cell death were measured. These results were compared against results obtained from well-characterized acetaminophen overdose patients., Results: At peak injury, ALT measured 4082±606 U/L and gradually decreased over 5 days, corresponding to the clinically observed pattern of hypoxic hepatitis. Levels of GDH showed a similar pattern, but neither ALT nor GDH were significantly higher in these patients than in acetaminophen patients. Plasma levels of DNA fragments mimicked hepatocellular injury as measured by ALT and miRNA-122. Interestingly, we found a significant increase in caspase-cleaved cytokeratin-18; however, the full-length form greatly exceeded the cleaved form at the time of maximum injury (45837±12085 vs 2528±1074 U/L). We also found an increase in acHMGB1 at later time points indicating a possible role of inflammation, but cytokine levels at these times were actually decreased relative to early time points., Conclusions: The mechanism of injury following hypoxic hepatitis involves mitochondrial damage and DNA fragmentation. Importantly, necrosis, rather than apoptosis, is the main mode of cell death., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The aim of this study was to describe compliance with select quality indicators and assess organ-specific dysfunction in a childhood-onset systemic lupus erythematosus population by using a validated damage index and to evaluate associations between compliance with quality indicators and disease damage. A retrospective chart review was performed on patients diagnosed with systemic lupus erythematosus prior to age 18 followed at a single center in the USA from 1999 to 2012 (n = 75). Data regarding quality indicators and outcome variables, including the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, were collected. The median disease duration was 3.8 years. The proportion of patients or patient-years in which care complied with the proposed quality measures was 94.4% for hydroxychloroquine use, 84.3% for vitamin D recommendation,75.8% for influenza vaccination (patient-years), 67.2% for meningococcal vaccination, 49.0% for ophthalmologic examination (patient-years), 31.7% for pneumococcal vaccination, and 28.6% for bone mineral density evaluation. Disease damage was present in 41.3% of patients at last follow-up, with an average damage index score of 0.81. Disease damage at last follow-up was associated with minority race/ethnicity (p = 0.008), bone mineral density evaluation (p = 0.035), and vitamin D recommendation (p = 0.018). Adherence to quality indicators in a childhood-onset systemic lupus erythematosus population is varied, and disease damage is prevalent. This study highlights the importance of quality improvement initiatives aimed at optimizing care delivery to reduce disease damage in pediatric lupus patients.

Chronic liver disease is the fifth leading cause of death worldwide and represents a major burden for the health care community. Cirrhosis is a progressive disease resulting in end-stage liver failure, which in the absence of liver transplantation is fatal. Acute-on-chronic liver failure carries high short-term mortality but is potentially reversible. Viral hepatitis, alcohol, and nonalcoholic fatty liver disease remain the principal causes of liver disease. Though treatments exist for hepatitis B and C, they remain unavailable to many with these diseases. This article reviews the epidemiology of advanced liver disease and the concept of acute-on-chronic liver failure., (Copyright © 2016 Elsevier Inc. All rights reserved.)