Search

Paediatric Intensive Care Units (PICU) are complex interdisciplinary environments where challenging, high stakes decisions are frequently encountered. We assert that appropriate decisions are more likely to be made if the decision-making process is comprehensive, reasoned, and grounded in thoughtful deliberation. Strategies to overcome barriers to high quality decision-making including, cognitive and implicit bias, group think, inadequate information gathering, and poor quality deliberation should be incorporated. Several general frameworks for decision-making exist, but specific guidance is scarce. In this paper, we provide specific guidance on collaborative complex decision-making for PICUs. The proposed approach is on principles of procedural justice and pragmatic hermeneutics. The process encompasses set-up/planning, information gathering, question formulation, analysis (perspectives, values, and principles), action plan development, decision documentation, and a review and appeal mechanism. The process can be adapted to suit other clinical contexts. Research evaluating the process, exploring how best to develop education for clinicians, and how to build a culture that values high quality deliberation, is worthwhile., (© 2024. Journal of Bioethical Inquiry Pty Ltd.)

Objectives: To study the impact of social determinants of health (SDoH) on pediatric extracorporeal membrane oxygenation (ECMO) outcomes., Design, Setting, and Patients: Retrospective study of children (< 18 yr) supported on ECMO (October 1, 2015 to March 1, 2021) using Pediatric Health Information System (44 U.S. children's hospitals). Patients were divided into five diagnostic categories: neonatal cardiac, pediatric cardiac, neonatal respiratory, pediatric respiratory, and sepsis. SDoH included the Child Opportunity Index (COI; higher indicates social advantage), race, ethnicity, payer, and U.S. region. Children without COI were excluded. Diagnostic category-specific clinical variables related to baseline health and illness severity were collected., Interventions: None., Measurements and Main Results: Children supported on ECMO experienced a 33% in-hospital mortality (2863/8710). Overall, children with lower COI, "other" race, Hispanic ethnicity, public insurance and from South or West regions had greater mortality. Associations between SDoH and ECMO outcomes differed between diagnostic cohorts. Bivariate analyses found that only pediatric cardiac patients had an association between COI or race and mortality. Multivariable logistic regression analyses examined relationships between SDoH, clinical variables and mortality within diagnostic categories. Pediatric cardiac patients had 5% increased odds of death (95% CI, 1.01-1.09) for every 10-point decrement in COI, while Hispanic ethnicity was associated with higher survival (adjusted odds ratio [aOR] 0.72 [0.57-0.89]). Children with heart disease from the highest COI quintile had less cardiac-surgical complexity and earlier cannulation. Independent associations with mortality were observed in sepsis for Black race (aOR 1.62 [1.06-2.47]) and other payer in pediatric respiratory patients (aOR 1.94 [1.23-3.06])., Conclusions: SDoH are statistically associated with pediatric ECMO outcomes; however, associations differ between diagnostic categories. Influence of COI was observed only in cardiac patients while payer, race, and ethnicity results varied. Further research should investigate differences between diagnostic cohorts and age groups to understand drivers of inequitable outcomes., Competing Interests: Dr. Newburger’s institution received funding from Pfizer, Bristol Myers Squibb, and Daiichi-Sankyo; she received funding from Bristol Myers Squibb, Novartis, and UpToDate; she disclosed that she is on the Steering Committee for ENOBLATE trial. Dr. Thiagarajan’s institution received funding from the U.S. Department of Defense Clinical Trial (award W81XWH2210301); he received funding from the Society of Critical Care Medicine and Extracorporeal Life Support Organization. Dr. Moynihan received funding from Edwards Life Sciences. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Race-conscious research identifies health disparities with 1) rigorous and responsible data collection, 2) intentionality and considered analyses, and 3) interpretation of results that advance health equity. Individual registries must overcome specific challenges to promote race-conscious research, and this paper describes ways to achieve this with a focus on the international Extracorporeal Life Support Organization (ELSO) registry. This article reviews ELSO registry publications that studied race with outcomes to consider whether research outputs align with race-conscious concepts and describe the direction of associations reported. Studies were identified via secondary analysis of a comprehensive scoping review on ECMO disparities. Of 32 multicenter publications, two (6%) studied race as the primary objective. Statistical analyses, confounder adjustment, and inclusive, antibiased language were inconsistently used. Only two (6%) papers explicitly discussed mechanistic drivers of inequity such as structural racism, and five (16%) discussed race variable limitations or acknowledged unmeasured confounders. Extracorporeal Life Support Organization registry publications demonstrated more adverse ECMO outcomes for underrepresented/minoritized populations than non-ELSO studies. With the objective to promote race-conscious ELSO registry research outputs, we provide a comprehensive understanding of race variable limitations, suggest reasoned retrospective analytic approaches, offer ways to interpret results that advance health equity, and recommend practice modifications for data collection., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.)

Objective: To examine specialty pediatric palliative care (SPPC) and end-of-life care for children with advanced heart disease in Alabama, including rates of and disparities in SPPC involvement., Study Design: We performed a retrospective study from electronic health records of children (≤21 years at death) who died with advanced heart disease at a single institution between 2012 and 2019 (n = 128). The main outcome was SPPC consult; we assessed clinical and sociodemographic factors associated with SPPC., Results: The median age at death was 6 months (IQR = 1-25 months) with 80 (63%) ≤1 year; 46% were Black and 45% non-Hispanic White. Seventy (55%) children had critical congenital heart disease, 45 (35%) non-critical congenital heart disease, and 13 (10%) acquired heart disease. Twenty-nine children (22%) received SPPC. Children ≤1 year at time of death and Black children were less likely to receive SPPC (aOR [95% CI]: 0.2 [0.1-0.6], reference >1 year; 0.2 [0.1-0.7], reference non-Hispanic White). SPPC was associated with death while receiving comfort-focused care (30.6 [4.5-210]), do not resuscitate orders (8.2 [2.1-31.3]), and hospice enrollment (no children without SPPC care were enrolled in hospice) but not medically intense end-of-life care (intensive care unit admission, mechanical ventilation, hemodialysis, or cardiopulmonary resuscitation) or death outside the intensive care unit., Conclusions: Children dying with advanced heart disease in Alabama did not have routine SPPC involvement; infants and Black children had lower odds of SPPC. SPPC was associated with more comfort-focused care. Disparities in SPPC utilization for children with advanced heart disease need further examination., Competing Interests: Declaration of Competing Interest This study was supported by a Palliative Research Enhancement Project Award (through the University of Alabama's Center for Palliative and Supportive Care) to Emily Johnston. The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To derive systematic-review informed, modified Delphi consensus regarding the medications used for anticoagulation for pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE (PEACE)., Data Sources: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021., Study Selection: Included studies assessed anticoagulation used in pediatric ECMO., Data Extraction: Two authors reviewed all citations independently, with a third reviewer adjudicating any conflicts. Eighteen references were used for data extraction as well as for creation of recommendations. Evidence tables were constructed using a standardized data extraction form., Data Synthesis: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements, or good practice statements for anticoagulation during pediatric ECMO. A web-based modified Delphi process was used to build consensus via the Research and Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. Two recommendations, two consensus statements, and one good practice statement were developed, and, in all, agreement greater than 80% was reached., Conclusions: There is insufficient evidence to formulate optimal anticoagulation therapy during pediatric ECMO. Additional high-quality research is needed to inform evidence-based practice for anticoagulation during pediatric ECMO., Competing Interests: The Executive Committee (Drs. Alexander, Muszynski, Bembea, Cheifetz, Steiner, and Barbaro) served as arbitrators for conflict of interest management. Dr. Alexander’s institution received funding from Novartis (ProspectiveTrial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF [PANORAMA-HF]). Dr. Sloan commenced employment with CSL Behring after the consensus process was complete. Dr. Patregnani discloses consultation payments from MNK Pharmaceuticals and Pfizer. Dr. Dalton discloses she is a consultant for Innovative Extracorporeal Membrane Oxygenation Concepts, Hemocue Entegrion, and Medtronic. Dr. Ryerson received an honorarium from the Instrumentation Laboratory for consultation work. Drs. Brandão, Monagle, Ryerson, Alexander, and Dalton disclosed the off-label product use of direct thrombin inhibitors for pediatric ECMO anticoagulation. Dr. Muszynski’s institution received funding from the National Institutes of Health (NIH). Drs. Muszynski and Alexander received support for article research from the NIH. Dr. Alexander’s institution received funding from the National Institute of Child Health and Human Development (R13HD104432), ELSO, and Novartis. Dr. Dalton received funding from Innovative ECMO Concepts, Entegrion, and Hemocue. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: To derive systematic-review informed, modified Delphi consensus regarding antifibrinolytic and adjunct hemostatic agents in neonates and children supported with extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE consensus conference., Data Sources: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021., Study Selection: Use of antifibrinolytics (epsilon-aminocaproic acid [EACA] or tranexamic acid), recombinant factor VII activated (rFVIIa), or topical hemostatic agents (THAs)., Data Extraction: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Eleven references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form., Measurements and Main Results: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One weak recommendation and three consensus statements are presented., Conclusions: Evidence supporting recommendations for administration of antifibrinolytics (EACA or tranexamic acid), rFVIIa, and THAs were sparse and inconclusive. Much work remains to determine effective and safe usage strategies., Competing Interests: The Executive Committee (Drs. Alexander, Muszynski, Bembea, Cheifetz, Steiner, and Barbaro) served as arbitrators for conflict of interest management. Dr. Alexander’s institution received funding from Novartis (Prospective Trial to Assess the Angiotensin Receptor Blocker NeprilysinInhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatmentof Pediatric HF [PANORAMA-HF]). Dr. Ryerson received an honorarium from the Instrumentation Laboratory for consultation work. Dr. Ryerson disclosed the off-label product use of antifibrinolytic agents (epsilon-aminocaproic acid and tranexamic acid) and topical hemostatic agents. Drs. Alexander and Muszynski’s institutions received funding from the National Institutes of Health (NIH) and received support for article research from the NIH. Dr. Alexander’s institution received funding from the Extracorporeal Life Support Organization and Novartis. Dr. Steiner’s institution received funding from the Department of Defense; she received funding from Octapharma and Medtronic; she disclosed she was on the Data Safety and Monitoring Board for the Pumps for Kids, Infants and Neonates (PumpKIN) Trial; she disclosed the off-label product use of rFVIIa, Kcentra, antithrombin, tranexamic acid, and Amicar. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference., Data Sources: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children., Study Selection: The management of ECMO anticoagulation for critically ill children., Data Extraction: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts., Data Synthesis: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements., Conclusions: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials., Competing Interests: Drs. Alexander’s and Muszynski’s institutions received funding from the National Institutes of Health (NIH). Drs. Alexander, Bembea, Himebauch, Barbaro, and Muszynski received support for article research from the NIH. Drs. Alexander’s and Bembea’s institutions received funding from the Extracorporeal Life Support Organization (ELSO). Dr. Alexander’s institution received funding from Novartis (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF [PANORAMA-HF]). Dr. Alexander disclosed that she is Treasurer of the Board of Directors of ELSO, past Co-Chair of Pediatric Extracorporeal Membrane Oxygenation (Pedi-ECMO). Dr. Bembea’s institution received funding from the National Institute of Neurologic Disorders and Stroke and a Grifols Investigator Sponsored Research Grant. Dr. Cheifetz received funding from UptoDate. Dr. Dalton received funding from Innovative Extracorporeal Membrane Oxygenation (ECMO) Concepts, Medtronic, Entegrion, and Hemocue. Drs. Dalton, Ozment, Barbaro, Almond, Brandão, Baumann Kreuziger, Paden, and Ryerson disclosed the off-label product use of pediatric ECMO-related medications for anticoagulation. Dr. Himebauch’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI) (K23HL153759). Drs. Karam’s and Nellis’s institutions received funding from the NHBLI (R34HL159119). Dr. Ozment received funding from Kaufman & Canoles, Social Cascade, and Wiseman Ashworth Law Group. Dr. Steiner’s institution received funding from the Department of Defense (DoD); she received funding from Medtronic and Octapharma; she disclosed that she is a Pumps for Kids, Infantsand Neonates (PumpKIN) trial Data Safety and Monitoring Board member. Dr. Alexander’s and Thiagarajan’s institution received funding from the DoD Clinical Trial Award for Trial of Indication-Based Transfusion of RBCs in ECMO trial (W81XWH2210301). Dr. Thiagarajan received funding from Society of Critical Care Medicine and ELSO. Dr. Zantek disclosed that she is a Board Member and Vice President of the North American Specialized Coagulation Laboratory Association and Board Member of the American Society for Apheresis, the External Quality Assurance in Thrombosis and Hemostasis, and Blood Network subgroup of Pediatric Acute Lung Injury and Sepsis Investigators groups; she disclosed that her spouse is an employee of Boston Scientific and owns stock in Endo International PLC. Dr. Barbaro’s institution received funding from the NHLBI (R01 HL153519 and K12 HL138039); he disclosed that he is ELSO Board of Directors and Pedi-ECMO Co-Chair. Dr. Emani received funding from Chiesi Pharma. Dr. Hyslop disclosed he is Co-Chair of ELSO Registry Database Development Committee and Coordinator Liaison to ELSO Steering Committee. Dr. Baumann Kreuziger received funding from the Health Resources and Services Administration Vaccine Injury Compensation Program. Dr. Paden disclosed that he is past president and board member of ELSO. Dr. Ryerson received an honorarium from Instrumentation Laboratory for consultation work. Dr. Sloan commenced employment with CSL Behring after the consensus process was complete. Dr. Patregnani received funding from Mallinckrodt; he discloses consultation payments from MNK pharmaceuticals and Pfizer. The Executive Committee (Drs. Alexander, Muszynski, Bembea, Cheifetz, Steiner, and Barbaro) served as arbitrators for conflict-of-interest management. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: To identify and prioritize research questions for anticoagulation and hemostasis management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus., Data Sources: Systematic review was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial consensus conferences of international, interprofessional experts in the management of ECMO for critically ill neonates and children., Study Selection: The management of ECMO anticoagulation for critically ill neonates and children., Data Extraction: Within each of the eight subgroups, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts., Data Synthesis: Following the systematic review of MEDLINE, EMBASE, and Cochrane Library databases from January 1988 to May 2021, and the consensus process for clinical recommendations and consensus statements, PEACE panel experts constructed research priorities using the Child Health and Nutrition Research Initiative methodology. Twenty research topics were prioritized, falling within five domains (definitions and outcomes, therapeutics, anticoagulant monitoring, protocolized management, and impact of the ECMO circuit and its components on hemostasis)., Conclusions: We present the research priorities identified by the PEACE expert panel after a systematic review of existing evidence informing clinical care of neonates and children managed with ECMO. More research is required within the five identified domains to ultimately inform and improve the care of this vulnerable population., Competing Interests: Drs. Muszynski and Alexander’s institutions received funding from the National Institutes of Health (NIH). Drs. Muszynski, Bembea, Himebauch, Barbaro, and Alexander received support for article research from the NIH. Dr. Bembea’s institution received funding from the National Institute of Neurologic Disorder and Stroke (R01NS106292) and a Grifols Investigator Sponsored Research Grant. Drs. Bembea, Steiner, and Thiagarajan’s institutions received funding from the Department of Defense. Dr. Cheifetz received funding from UptoDate. Dr. Dalton received funding from Innovative Extracorporeal Membrane Oxygenation (ECMO) Concepts, Entegrion, and Hemocue; she disclosed the off-label product use of ECMO equipment and drugs for anticoagulation. Dr. Himebauch receives support from the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number K23HL153759. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Dr. Said acknowledges research support from the Children’s Discovery Institute Faculty Development Award at Washington University in St. Louis. Dr. Ozment received funding from Kaufman & Canoles Law Firm, Wiseman Ashworth Law Group, and Social Cascade; she disclosed the off-label product use of Heparin and bivalirudin use in neonatal and pediatric patients on ECMO. Dr. Steiner received funding from Octapharma, MedTronic, and PumpKIN DSMB; she disclosed the off-label product use of rFVIIA, TXA, Amicar, Kcentra. Dr. Thiagarajan received funding from the Society of Critical Care Medicine and the Extracorporeal Life Support Organization (ELSO). Dr. Zantek received funding from the North American Specialized Coagulation Laboratory Association (NASCOLA), the American Society for Apheresis (ASFA), and BloodNet; she disclosed that she is a Board Member of External Quality Assurance in Thrombosis and Hemostasis, a committee member of NASCOLA, ASFA, the Association for the Advancement of Blood and Biotherapies, the College of American Pathologists, and the International Society for Laboratory Hematology; she disclosed that her spouse is an employee of Boston Scientific and has a financial interest in Boston Scientific and Endo International. Dr. Barbaro’s institution received funding from the NIH (R01 HL153519 and K12 HL138039); he disclosed that he is a Board Member for ELSO and Co-Chair for Pedi-ECMO. Dr. Alexander’s institution received funding from ELSO and Novartis. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: To derive systematic-review informed, modified Delphi consensus regarding prophylactic transfusions in neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE., Data Sources: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2020, with an update in May 2021., Study Selection: Included studies assessed use of prophylactic blood product transfusion in pediatric ECMO., Data Extraction: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Thirty-three references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form., Measurements and Main Results: The evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for prophylactic transfusion strategies for children supported with ECMO. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. We developed two good practice statements, 4 weak recommendations, and three expert consensus statements., Conclusions: Despite the frequency with which pediatric ECMO patients are transfused, there is insufficient evidence to formulate evidence-based prophylactic transfusion strategies., Competing Interests: The Executive Committee (Drs. Alexander, Muszynski, Bembea, Cheifetz, Steiner, and Barbaro) served as arbitrators for conflict of interest management. Dr. Alexander’s institution received funding from Novartis (consultant on the end-point adjudication committee for Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF [PANORAMA-HF] clinical trial). Dr. Sloan commenced employment with CSL Behring after the consensus process was complete. Dr. Kneyber received funding from Metran. Drs. Alexander and Muszynski’s institutions received funding from the National Institutes of Health (NIH); they received support for article research from the NIH. Dr. Alexander’s institution received funding from the Extracorporeal Life Support Organization and Novartis. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

While many experts in pediatric cardiology have emphasized the importance of palliative care involvement, very few studies have assessed the influence of specialty pediatric palliative care (SPPC) involvement for children with heart disease. We conducted a systematic review using keywords related to palliative care, quality of life and care-satisfaction, and heart disease. We searched PubMed, EMBASE, CINAHL, CENTRAL and Web of Science in December 2023. Screening, data extraction and methodology followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Pairs of trained reviewers independently evaluated each article. All full texts excluded from the review were hand-screened for eligible references including systematic reviews in general pediatric populations. Two reviewers independently extracted: (1) study design; (2) methodology; (2) setting; (3) population; (4) intervention/exposure and control definition; (5) outcome measures; and (6) results. Of 4059 studies screened, 9 met inclusion criteria including two with overlapping patient data. Study designs were heterogenous, including only one randomized control and two historical control trials with SPPC as a prospective intervention. Overall, there was moderate to high risk of bias. Seven were single centers studies. In combined estimates, patients who received SPPC were more likely to have advance care planning documented (RR 2.7, [95%CI 1.6, 4.7], p < 0.001) and resuscitation limits (RR 4.0, [2.0, 8.1], p < 0.001), while half as likely to have active resuscitation at end-of-life ([0.3, 0.9], p = 0.032). For parental stress, receipt of SPPC improved scores by almost half a standard deviation (RR 0.48, 95%CI 0.10, 0.86) more than controls. Ultimately, we identified a paucity of high-quality data studying the influence of SPPC; however, findings correlate with literature in other pediatric populations. Findings suggest benefits of SPPC integration for patients with heart disease and their families., (© 2024. The Author(s).)

Objectives: Understanding factors influencing quality of pediatric end-of-life (EOL) care is necessary to identify interventions to improve family and staff experiences. We characterized pediatric cardiac ICU (PCICU) staff free-text survey responses to contextualize patterns in quality of dying and death (QODD) scoring., Design: This mixed methods study reports on a cross-sectional survey of PCICU staff involved in patient deaths., Setting: Single, quaternary PCICU from 2019-2021., Participants: Multidisciplinary staff (bedside nurses, allied health professionals, and medical practitioners) rated QODD and voluntarily added free-text responses. We derived descriptive categories of free-text responses using content analysis. Response sentiment was classified as positive, negative or both positive and negative. We compared category and sentiment frequency by discipline, EOL medical intensity, years of experience and QODD score quartiles., Interventions: None., Measurements and Main Results: Of 60 deaths and 713 completed staff surveys, 269 (38%) contained free-text responses, including 103 of 269 (38%) from nurses. Of six qualitative categories (i.e., relational dynamics, clinical circumstances, family experiences, emotional expressions, temporal conditions, and structural/situational factors), relational dynamics was most frequent (173 responses). When compared by discipline, family experiences were more common in nursing responses than medical practitioners or allied health. High intensity was associated with infrequent discussion of family experience and greater focus on temporal conditions and clinical circumstances. Emotional expressions and temporal conditions were more common in lowest QODD quartile surveys. Although 45% staff responses contained both sentiments, relational dynamics and family experiences were more likely positive. Negative sentiments were more common in the lowest QODD quartile surveys and responses containing temporal conditions or structural/situational factors., Conclusions: Synergistic relationships between the multidisciplinary team and family shaped clinician's positive responses. Attention to team dynamics may be a crucial ingredient in interventions to improve EOL care. Our data support that team-based education initiatives should consider differential foci between disciplines and EOL characteristics., Competing Interests: Dr. Broden’s, Ms. Bailey’s, and Dr. Moynihan’s institutions received funding from the New England Congenital Cardiology Research Foundation (NECCRF). Ms. Bailey and Dr. Moynihan received support for article research from the NECCRF. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Introduction: Advances in medical technology have led to both clinical and philosophical challenges in defining death. Highly publicized cases have occurred when families or communities challenge a determination of death by the irreversible cessation of neurologic function (brain death). Parallels can be drawn in cases where an irreversible cessation of cardiopulmonary function exists, in which cases patients are supported by extracorporeal cardiopulmonary support, such as extracorporeal membrane oxygenation (ECMO)., Analysis: Two cases and an ethical analysis are presented which compare and contrast contested neurologic determinations of death and refusal to accept the irreversibility of an imminent death by cardiopulmonary standards. Ambiguities in the Uniform Determination of Death Act are highlighted, as it can be clear, when supported by ECMO, that a patient could have suffered the irreversible cessation of cardiopulmonary function yet still be alive (e.g., responsive and interactive). Parallel challenges with communication with families around the limits of medical technology are discussed., Discussion: Cases that lead to conflict around the removal of technology considered not clinically beneficial are likely to increase. Reframing our goals when death is inevitable is important for both families and the medical team. Building relationships and trust between all parties will help families and teams navigate these situations. All parties may require support for moral distress. Suggested approaches are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Moynihan, Taylor, Siegel, Nassar, Lelkes and Morrison.)

Interactions between lineage-determining and activity-dependent transcription factors determine single-cell identity and function within multicellular tissues through incompletely known mechanisms. By assembling a single-cell atlas of chromatin state within human islets, we identified β cell subtypes governed by either high or low activity of the lineage-determining factor pancreatic duodenal homeobox-1 (PDX1). β cells with reduced PDX1 activity displayed increased chromatin accessibility at latent nuclear factor κB (NF-κB) enhancers. Pdx1 hypomorphic mice exhibited de-repression of NF-κB and impaired glucose tolerance at night. Three-dimensional analyses in tandem with chromatin immunoprecipitation (ChIP) sequencing revealed that PDX1 silences NF-κB at circadian and inflammatory enhancers through long-range chromatin contacts involving SIN3A. Conversely, Bmal1 ablation in β cells disrupted genome-wide PDX1 and NF-κB DNA binding. Finally, antagonizing the interleukin (IL)-1β receptor, an NF-κB target, improved insulin secretion in Pdx1 hypomorphic islets. Our studies reveal functional subtypes of single β cells defined by a gradient in PDX1 activity and identify NF-κB as a target for insulinotropic therapy., Competing Interests: Declaration of interests M.P. is currently affiliated with Ionis Pharmaceuticals, Inc., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To describe associations between the timing of tracheostomy and patient characteristics or outcomes in the cardiac ICU (CICU)., Design: Single-institution retrospective cohort study., Setting: Freestanding academic children's hospital., Patients: CICU patients with tracheostomy placed between July 1, 2011, and July 1, 2020., Interventions: We compared patient characteristics and outcomes between early and late tracheostomy based on the duration of positive pressure ventilation (PPV) before tracheostomy placement, fitting a receiver operating characteristic curve for current survival to define a cutoff., Measurements and Main Results: Sixty-one patients underwent tracheostomy placement (0.5% of CICU admissions). Median age was 7.8 months. Eighteen patients (30%) had single ventricle physiology and 13 patients (21%) had pulmonary vein stenosis (PVS). Primary indications for tracheostomy were pulmonary/lower airway (41%), upper airway obstruction (UAO) (31%), cardiac (15%), neuromuscular (4%), or neurologic (4%). In-hospital mortality was 26% with 41% survival at the current follow-up (median 7.8 [interquartile range, IQR 2.6-30.0] mo). Late tracheostomy was defined as greater than or equal to 7 weeks of PPV which was equivalent to the median PPV duration pre-tracheostomy. Patients with late tracheostomy were more likely to be younger, have single ventricle physiology, and have greater respiratory severity. Patients with early tracheostomy were more likely to have UAO or genetic comorbidities. In multivariable analysis, late tracheostomy was associated with 4.2 times greater mortality (95% CI, 1.9-9.0). PVS was associated with higher mortality (adjusted hazard ratio [HR] 5.2; 95% CI, 2.5-10.9). UAO was associated with lower mortality (adjusted HR 0.2; 95% CI, 0.1-0.5). Late tracheostomy was also associated with greater cumulative opioid exposure., Conclusions: CICU patients who underwent tracheostomy had high in-hospital and longer-term mortality rates. Tracheostomy timing decisions are influenced by indication, disease, genetic comorbidities, illness severity, and age. Earlier tracheostomy was associated with lower sedative use and improved adjusted survival. Tracheostomy placement is a complex decision demanding individualized consideration of risk-benefit profiles and thoughtful family counseling., Competing Interests: Ms. Roberts received funding from Boston Children’s Hospital; she disclosed that she is employed with Boston Children’s Hospital. Dr. Mastropietro received funding from Carle Foundation and Bioporto. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: To map the scope, methodological rigor, quality, and direction of associations between social determinants of health (SDoH) and extracorporeal membrane oxygenation (ECMO) utilization or outcomes., Data Sources: PubMed, Web of Science, Embase, and Cochrane Library databases were systematically searched for citations from January 2000 to January 2023, examining socioeconomic status (SES), race, ethnicity, hospital and ECMO program characteristics, transport, and geographic location (context) with utilization and outcomes (concept) in ECMO patients (population)., Study Selection: Methodology followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses scoping review extension. Two reviewers independently evaluated abstracts and full text of identified publications. Exclusion criteria included non-English, unavailable, less than 40 patients, and periprocedural or mixed mechanical support., Data Extraction: Content analysis used a standardized data extraction tool and inductive thematic analysis for author-proposed mediators of disparities. Risk of bias was assessed using the Quality in Prognosis Studies tool., Data Synthesis: Of 8,214 citations screened, 219 studies were identified. Primary analysis focuses on 148 (68%) including race/ethnicity/SES/payer variables including investigation of ECMO outcomes 114 (77%) and utilization 43 (29%). SDoH were the primary predictor in 15 (10%). Overall quality and methodologic rigor was poor with advanced statistics in 7%. Direction of associations between ECMO outcomes or utilization according to race, ethnicity, SES, or payer varied. In 38% adverse outcomes or lower use was reported in underrepresented, under-resourced or diverse populations, while improved outcomes or greater use were observed in these populations in 7%, and 55% had no statistically significant result. Only 26 studies (18%) discussed mechanistic drivers of disparities, primarily focusing on individual- and hospital-level rather than systemic/structural factors., Conclusions: Associations between ECMO utilization and outcomes with SDoH are inconsistent, complicated by population heterogeneity and analytic shortcomings with limited consideration of systemic contributors. Findings and research gaps have implications for measuring, analyzing, and interpreting SDoH in ECMO research and healthcare., Competing Interests: Dr. Kolwaite received funding from the Centers for Disease Control and Prevention. Dr. Barbaro’s institution received funding from the National Institutes of Health (NIH) (R01 HL153519); he received funding from the NIH (K12 HL138039); he received support for article research from the NIH; and he is the Extracorporeal Life Support Organization (ELSO) Registry Chair. Dr. Thiagarajan’s institution received funding from a grant from the U.S. Department of Defense for Clinical Trial in Extracorporeal Membrane Oxygenation (Trial of Indication-Based Transfusion of Red Blood Cells in ECMO); he received funding from the Society of Critical Care Medicine and the ELSO. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Strict visitor restrictions during the COVID-19 pandemic have been associated with staff moral distress in numerous clinical settings, yet little is known about effects on perceptions of pediatric end-of-life care., Objective: To determine the effect of COVID-19 visitor restrictions on perceptions of quality of dying and death., Methods: This was a cross-sectional survey of interdisciplinary staff caring for dying children in a cardiac intensive care unit with flexible visitation allowances compared with published policies reported in the literature at the time., Results: No significant difference in perceptions of quality of dying and death was found between the prepandemic and pandemic periods despite similar clinical care provision. The relatively less stringent allowances at end of life did not adversely affect staff risk for infection., Conclusions: The findings support affording some flexibility to visitation at end of life, which may mitigate negative staff perceptions of quality of dying and death. With the profound effects of COVID-19 on end-of-life care provision, these results may have implications for future global challenges., (©2023 American Association of Critical-Care Nurses.)

Background: Coronavirus disease (COVID-19) required innovative training strategies for emergent aerosol generating procedures in intensive care units. This manuscript summarizes institutional operationalization of COVID-specific training, standardized across four intensive care units., Methods & Results: An interdisciplinary team collaborated with the Simulator Program and OpenPediatrics refining logistics using process maps, walkthroughs and simulation. A multimodal approach to information dissemination, high-volume team training in modified resuscitation practices and technical skill acquisition included instructional videos, training superusers, small-group simulation using a flipped classroom approach with rapid cycle deliberate practice, interactive webinars, and cognitive aids. Institutional data on application of this model are presented., Conclusion: Success was founded in interdisciplinary collaboration, resource availability and institutional buy in., (© 2022 International Nursing Association for Clinical Simulation and Learning. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Are all children extracorporeal membrane oxygenation (ECMO) candidates? Navigating ECMO decisions represents an enormous challenge in pediatric critical care. ECMO cannulation should not be a default option as it will not confer benefit for "all" critically ill children; however, "all" children deserve well-considered decisions surrounding their ECMO candidacy. The complexity of the decision demands a systematic, "well-reasoned" and "dynamic" approach. Due to clinical urgency, this standard cannot always be met prior to initiation of ECMO. We challenge the paradigm of "candidacy" as a singular decision that must be defined prior to ECMO initiation. Rather, the determination as to whether ECMO is in the patient's best interest is applicable regardless of cannulation status. The priority should be on collaborative, interdisciplinary decision-making processes aligned with principles of transparency, relevant reasoning, accountability, review, and appeal. To ensure a robust process, it should not be temporally constrained by cannulation status. We advocate that this approach will decrease both the risk of not initiating ECMO in a patient who will benefit and the risk of prolonged, nonbeneficial support. We conclude that to ensure fair decisions are made in a patient's best interest, organizations should develop procedurally fair processes for ECMO decision-making that are not tied to a particular time point and are revisited along the management trajectory., Competing Interests: Dr. Jansen received funding from Ernst & Young. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Importance: Lack of pediatric end-of-life care quality indicators and challenges ascertaining family perspectives make staff perceptions valuable. Cardiac intensive care unit (CICU) interdisciplinary staff play an integral role supporting children and families at end of life., Objectives: To evaluate the Pediatric Intensive Care Unit Quality of Dying and Death (PICU-QODD) instrument and examine differences between disciplines and end-of-life circumstances., Design, Setting, and Participants: This cross-sectional survey included staff at a single center involved in pediatric CICU deaths from July 1, 2019, to June 30, 2021., Exposures: Staff demographic characteristics, intensity of end-of-life care (mechanical support, open chest, or cardiopulmonary resuscitation [CPR]), mode of death (discontinuation of life-sustaining therapy, treatment limitation, comfort care, CPR, and brain death), and palliative care involvement., Main Outcomes and Measures: PICU-QODD instrument standardized score (maximum, 100, with higher scores indicating higher quality); global rating of quality of the moment of death and 7 days prior (Likert 11-point scale, with 0 indicating terrible and 10, ideal) and mode-of-death alignment with family wishes., Results: Of 60 patient deaths (31 [52%] female; median [IQR] age, 4.9 months [10 days to 7.5 years]), 33 (55%) received intense care. Of 713 surveys (72% response rate), 246 (35%) were from nurses, 208 (29%) from medical practitioners, and 259 (36%) from allied health professionals. Clinical experience varied (298 [42%] ≤5 years). Median (IQR) PICU-QODD score was 93 (84-97); and quality of the moment of death and 7 days prior scores were 9 (7-10) and 5 (2-7), respectively. Cronbach α ranged from 0.87 (medical staff) to 0.92 (allied health), and PICU-QODD scores significantly correlated with global rating and alignment questions. Mean (SD) PICU-QODD scores were more than 3 points lower for nursing and allied health compared with medical practitioners (nursing staff: 88.3 [10.6]; allied health: 88.9 [9.6]; medical practitioner: 91.9 [7.8]; P < .001) and for less experienced staff (eg, <2 y: 87.7 [8.9]; >15 y: 91, P = .002). Mean PICU-QODD scores were lower for patients with comorbidities, surgical admissions, death following treatment limitation, or death misaligned with family wishes. No difference was observed with palliative care involvement. High-intensity care, compared with low-intensity care, was associated with lower median (IQR) rating of the quality of the 7 days prior to death (4 [2-6] vs 6 [4-8]; P = .001) and of the moment of death (8 [4-10] vs 9 [8-10]; P =.001)., Conclusions and Relevance: In this cross-sectional survey study of CICU staff, the PICU-QODD showed promise as a reliable and valid clinician measure of quality of dying and death in the CICU. Overall QODD was positively perceived, with lower rated quality of 7 days prior to death and variation by staff and patient characteristics. Our data could guide strategies to meaningfully improve CICU staff well-being and end-of-life experiences for patients and families.

Extracorporeal Membrane Oxygenation (ECMO) is associated with significant mortality. Provision of high-quality end-of-life (EOL) care for patients supported on ECMO entails specific physiological, pharmacological, and technical considerations. Limited guidance exists for clinicians on delivery of optimal EOL care on ECMO. In this article, we review the unique aspects of EOL care as they apply to ECMO support and propose a pragmatic, interdisciplinary framework for compassionate ECMO discontinuation in children and adults. The goal of compassionate ECMO discontinuation (CED) is to allow natural death from the underlying disease process while delivering high-quality EOL care to ensure a good death experience for patients and their families. The CED approach includes: 1) a family meeting to define goal-concordant EOL care and prepare families and patients for the dying process; 2) clinical preparation, including symptom management and discontinuation of other life-sustaining therapies; 3) technical aspects which necessarily vary according to patient factors and the circuit and cannulation strategy; and 4) bereavement support. The proposed CED considerations and checklist may serve as tools aiding provision of comprehensive, quality, individualized patient- and family-centered care for children and adults dying despite ECMO support. A structured CED may enhance EOL experiences for patients, family, and staff by providing a respectful and dignified death experience. Future research is required to determine feasibility and effectiveness of the framework, which must be adapted to the patient and institutional setting., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Children with heart disease often experience symptoms and medically intense end-of-life care. Our study explored bereaved parents' perceptions of a "good death" via a mail survey to 128 parents of children with heart disease who died in two centers. Parental perceptions of end-of-life circumstances were assessed by closed-ended questions including level of agreement with the question: "would you say your child experienced a good death?" and open-ended comments were contributed. Medical therapies at end-of-life and mode of death were retrieved through chart review. Of 50 responding parents, 44 (response rate: 34%) responded to the "good death" question; 16 (36%) agreed strongly, 15 (34%) agreed somewhat, and 30% disagreed (somewhat: 7, 16%; strongly: 6, 14%). Half the children were on mechanical support and 84% intubated at death. Of children with cardiopulmonary resuscitation (CPR) at end-of-life, 71% of parents disagreed with the "good death" question compared with 22% of parents whose child died following discontinuation of life-sustaining therapy or comfort measures (OR 9.1, 95% CI 1.3, 48.9, p < 0.01). Parent-reported circumstances associated with disagreement with the "good death" question included cure-oriented goals-of-care (OR 16.6, 95% CI 3.0, 87.8, p < 0.001), lack of advance care planning (ACP) (OR 12.4 95% CI 2.1, 65.3 p < 0.002), surprise regarding timing of death (OR 11.7, 95% CI 2.6, 53.4 p < 0.002), and experience of pain (OR 42.1, 95% CI 2.3, 773.7 p < 0.02). Despite high medical intensity, many bereaved parents of children with cardiac disease agree a "good death" was experienced. A "good death" was associated with greater preparedness, ACP, non-cure-oriented goals-of-care, pain control, and CPR avoidance., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The AngioVac System (AVS) extracts venous and pulmonary artery (PA) thrombi. We report modified use of the second-generation AVS with concurrent venoarterial extracorporeal membrane oxygenation (VA-ECMO) in a 10-year-old, 23 kg patient with failing Fontan circulation due to acute-on-chronic Fontan and PA thrombosis. Emergent femoral VA-ECMO was initiated for profound hypoxemia during cardiac catheterization. Fluoroscopy-guided thrombo-embolectomy was performed with AVS components. A two-venous limb inflow cannulation strategy was used; the AngioVac cannula (AVC) was positioned in the central PA and joined to the existing ECMO venous-limb. Thrombus extraction proceeded by clamping the ECMO venous-limb with the existing VA-ECMO centrifugal pump generating negative pressure to the AVC. Extracorporeal membrane oxygenation arterial-limb access was used for blood return. Settings to avoid cavitation were a maximal negative pressure of 100 mmHg using <3500 RPMs. To access the branch PAs, the AVC was replaced by a custom-modified 17 Fr arterial ECMO cannula. Clot retrieval was sufficient for improved clinical status enabling ECMO discontinuation within 24-hours, and discharge home 26-days later. This is the first description of successful subtotal thrombo-embolectomy with AVS components in a child with Fontan physiology concurrently supported on VA-ECMO, using one centrifugal pump. Although feasible, circuit modifications and close monitoring are required to avoid complications., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

The mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. Here, we developed a genetically sensitized small-molecule screen to identify druggable proteins and mechanistic pathways involved in circadian β-cell failure. Our approach was to generate β-cells expressing a nanoluciferase reporter within the proinsulin polypeptide to screen 2640 pharmacologically active compounds and identify insulinotropic molecules that bypass the secretory defect in CRISPR-Cas9-targeted clock mutant β-cells. We validated hit compounds in primary mouse islets and identified known modulators of ligand-gated ion channels and G-protein-coupled receptors, including the antihelmintic ivermectin. Single-cell electrophysiology in circadian mutant mouse and human cadaveric islets revealed ivermectin as a glucose-dependent secretagogue. Genetic, genomic, and pharmacological analyses established the P2Y1 receptor as a clock-controlled mediator of the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a diabetes target based upon a genetically sensitized phenotypic screen., Competing Interests: BM, BW, AT, KR, MN, YK, CO, JM, HL, PM, JB No competing interests declared, MP Mark Perelis is affiliated with Ionis Pharmaceuticals, Inc The author has no financial interests to declare, (© 2022, Marcheva et al.)

Despite advances in medicine, some children will always die; a decline in pediatric intensive care unit (PICU) mortality to zero will never be achieved. The mortality decline is correspondingly asymptotic, yet we remain preoccupied with mortality outcomes. Are we at the nadir, and are we, thus, as good as we can get? And what should we focus to benchmark our units, if not mortality? In the face of changing case-mix and rising complexity, dramatic reductions in PICU mortality have been observed globally. At the same time, survivors have increasing disability, and deaths are often characterized by intensive life-sustaining therapies preceded by prolonged admissions, emphasizing the need to consider alternate outcome measures to evaluate our successes and failures. What are the costs and implications of reaching this nadir in mortality outcomes? We highlight the failings of our fixation with survival and an imperative to consider alternative outcomes in our PICUs, including the costs for both patients that survive and die, their families, healthcare providers, and society including perspectives in low resource settings. We describe the implications for benchmarking, research, and training the next generation of providers.Conlusion: Although survival remains a highly relevant metric, as PICUs continue to strive for clinical excellence, pushing boundaries in research and innovation, with endeavors in safety, quality, and high-reliability systems, we must prioritize outcomes beyond mortality, evaluate "costs" beyond economics, and find novel ways to improve the care we provide to all of our pediatric patients and their families. What is Known: • The fall in PICU mortality is asymptotic, and a decline to zero is not achievable. Approaching the nadir, we challenge readers to consider implications of focusing on medical and technological advances with survival as the sole outcome of interest. What is New: • Our fixation with survival has costs for patients, families, staff, and society. In the changing PICU landscape, we advocate to pivot towards alternate outcome metrics. • By considering the implications for benchmarking, research, and training, we may better care for patients and families, educate trainees, and expand what it means to succeed in the PICU., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Context.—: Specific reference intervals (RIs) facilitate accurate interpretation of results. Coagulation assay results may vary by demographics and also between reagents and analyzers used. Current Thromboelastograph 6s (TEG 6s) Hemostasis Analyzer RIs were generated from adult samples., Objective.—: To generate reagent analyzer-specific pediatric RIs for TEG 6s and coagulation parameters., Design.—: A prospective, observational, single-center study of healthy children undergoing general anesthesia (January 3, 2017 to January 3, 2019). Venous blood samples were obtained for TEG 6s (Kaolin, Kaolin-Heparinase, Rapid and Functional Fibrinogen assays) and coagulation parameters (activated partial thromboplastin time, prothrombin time, thrombin clotting time, Echis time, antithrombin activity, and fibrinogen concentration using Instrumentation Laboratory ACL-TOP analyzers). Differences between activated partial thromboplastin time and prothrombin time reagents were investigated using mixed-effects regression, comparing maximum coefficients-of-variation with assay-specific allowable variation. RIs (lower/upper limits 2.5th of 97.5th percentiles) were generated using the following 2 methods: within discrete age-groups (neonates [<1 month], infants [1 month-1 year], young children [1-5 years], older children [6-10 years], and adolescents [11-16 years]), and modeled as functions of age and/or sex using quantile regression, including significant fractional polynomial and interaction terms., Results.—: Variation between prothrombin time and activated partial thromboplastin time assays using different reagents was clinically significant. Reagent-analyzer specific pediatric RIs were generated using data from 254 children. Discrete and model-based RIs varied by age for all coagulation parameters and TEG 6s variables in all assays., Conclusions.—: We report reagent-analyzer specific pediatric RIs for TEG 6s and coagulation parameters. Observed variation reinforces recommendations for laboratory-specific RIs. These findings improve accuracy of interpretation of clinical results, provide a foundation for comparison and validation of tests in pathology, and illustrate feasibility and advantages of model-based RI approaches.

Objectives: Pediatric extracorporeal membrane oxygenation is associated with significant morbidity and mortality. We sought to summarize literature on communication and decision-making, end-of-life care, and ethical issues to identify recommended approaches and highlight knowledge gaps., Data Sources: PubMed, Embase, Web of Science, and Cochrane Library., Study Selection: We reviewed published articles (1972-2020) which examined three pediatric extracorporeal membrane oxygenation domains: 1) decision-making or communication between clinicians and patients/families, 2) ethical issues, or 3) end-of-life care., Data Extraction: Two reviewers independently assessed eligibility using Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology., Data Synthesis: Of 2,581 publications screened, we identified one systematic review and 35 descriptive studies. No practical guides exist for communication and decision-making in pediatric extracorporeal membrane oxygenation. Conversation principles and parent/clinician perspectives are described. Ethical issues related to consent, initiation, discontinuation, resource allocation, and research. No patient-level synthesis of ethical issues or end-of-life care in pediatric extracorporeal membrane oxygenation was identified., Conclusions: Despite numerous ethical issues reported surrounding pediatric extracorporeal membrane oxygenation, we found limited patient-level research and no practical guides for communicating with families or managing extracorporeal membrane oxygenation discontinuation., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Decision-making surrounding extracorporeal membrane oxygenation initiation and decannulation has become a key challenge in critical care. Nuanced communication skills and transparent discussions about prognosis are imperative during this lifesaving, yet high-risk and burdensome intervention. Serious illness conversation guides are proving beneficial for patients, families and staff to communicate uncertainty and facilitate shared decision-making toward goal-concordant care. While the literature emphasizes the imperative to provide guidance for clinicians, no practical guide exists for communicating serious illness and prognostic uncertainty when managing children supported with extracorporeal membrane oxygenation and their families. To address this gap, we propose a structured conversation guide for critical early timepoints during pediatric extracorporeal membrane oxygenation support relevant for all cannulations and subsequent iterative discussions toward decannulation. The overarching approach defines extracorporeal membrane oxygenation as a bridge or temporary support device, part of a larger therapeutic effort toward a specific goal or goals. The Day 0 talk at extracorporeal membrane oxygenation initiation is brief, disclosing the serious nature of needing this level of support, and sets clear expectations toward a goal. The Day 1 talk provides further details about benefits and burdens of extracorporeal membrane oxygenation, cultivates prognostic awareness about potential outcomes and elicits families' goals of care with iterative discussions about how extracorporeal membrane oxygenation may promote these goals. If extracorporeal membrane oxygenation is no longer effective to achieve the intended goal, recommendations are provided for discontinuation of support. When death is anticipated or possible, end-of-life planning, contingencies, and escalation limits should be discussed. The communication framework presented can be adapted to unique institutional and clinical settings. Future research is required to investigate utility and potential barriers to implementation. We anticipate that structured conversations during extracorporeal membrane oxygenation support will facilitate clear expectations toward a common treatment goal, foster therapeutic relationships, ensure clinician alignment and consistent language, mitigate communication gaps, support bereavement, and minimize conflict., Competing Interests: Dr. Alexander’s institution received funding from Novartis; she received funding from Instrumentation Laboratories; she disclosed the off-label product use of extracorporeal membrane oxygenation. 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 the World Federation of Pediatric Intensive and Critical Care Societies.)

These guidelines are applicable to neonates and children with cardiac failure as indication for extracorporeal life support. These guidelines address patient selection, management during extracorporeal membrane oxygenation, and pathways for weaning support or bridging to other therapies. Equally important issues, such as personnel, training, credentialing, resources, follow-up, reporting, and quality assurance, are addressed in other Extracorporeal Life Support Organization documents or are center-specific., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ELSO 2021.)

Objectives: With evidence of benefits of pediatric palliative care (PPC) integration, we sought to characterize subspecialty PPC referral patterns and end of life (EOL) care in pediatric advanced heart disease (AHD)., Methods: In this retrospective cohort study, we compared inpatient pediatric (<21 years) deaths due to AHD in 2 separate 3-year epochs: 2007-2009 (early) and 2015-2018 (late). Demographics, disease burden, medical interventions, mode of death, and hospital charges were evaluated for temporal changes and PPC influence., Results: Of 3409 early-epoch admissions, there were 110 deaths; the late epoch had 99 deaths in 4032 admissions. In the early epoch, 45 patients (1.3% admissions, 17% deaths) were referred for PPC, compared with 146 late-epoch patients (3.6% admissions, 58% deaths). Most deaths (186 [89%]) occurred in the cardiac ICU after discontinuation of life-sustaining therapy (138 [66%]). Medical therapies included ventilation (189 [90%]), inotropes (184 [88%]), cardiopulmonary resuscitation (68 [33%]), or mechanical circulatory support (67 [32%]), with no temporal difference observed. PPC involvement was associated with decreased mechanical circulatory support, ventilation, inotropes, or cardiopulmonary resuscitation at EOL, and children were more likely to be awake and be receiving enteral feeds. PPC involvement increased advance care planning, with lower hospital charges on day of death and 7 days before (respective differences $5058 [ P = .02] and $25 634 [ P = .02])., Conclusions: Pediatric AHD deaths are associated with high medical intensity; however, children with PPC consultation experienced substantially less invasive interventions at EOL. Further study is warranted to explore these findings and how palliative care principles can be better integrated into care., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Objectives: Hemoptysis is uncommon in children, even among the critically ill, with a paucity of epidemiological data to inform clinical decision-making. We describe hemoptysis-associated ICU admissions, including those who were critically ill at hemoptysis onset or who became critically ill as a result of hemoptysis, and identify predictors of mortality., Design: Retrospective cohort study. Demographics, hemoptysis location, and management were collected. Pediatric Logistic Organ Dysfunction-2 score within 24 hours of hemoptysis described illness severity. Primary outcome was inhospital mortality., Setting: Quaternary pediatric referral center between July 1, 2010, and June 30, 2017., Patients: Medical/surgical (PICU), cardiac ICU, and term neonatal ICU admissions with hemoptysis during or within 24 hours of ICU admission., Interventions: No intervention., Measurements and Main Results: There were 326 hemoptysis-associated ICU admissions in 300 patients. Most common diagnoses were cardiac (46%), infection (15%), bronchiectasis (10%), and neoplasm (7%). Demographics, interventions, and outcomes differed by diagnostic category. Overall, 79 patients (26%) died inhospital and 109 (36%) had died during follow-up (survivor mean 2.8 ± 1.9 yr). Neoplasm, bronchiectasis, renal dysfunction, inhospital hemoptysis onset, and higher Pediatric Logistic Organ Dysfunction-2 score were independent risk factors for inhospital mortality (p < 0.02). Pharmacotherapy (32%), blood products (29%), computerized tomography angiography (26%), bronchoscopy (44%), and cardiac catheterization (36%) were common. Targeted surgical interventions were rare. Of survivors, 15% were discharged with new respiratory support. Of the deaths, 93 (85%) occurred within 12 months of admission. For patients surviving 12 months, 5-year survival was 87% (95% CI, 78-92) and mortality risk remained only for those with neoplasm (log-rank p = 0.001)., Conclusions: We observed high inhospital mortality from hemoptysis-associated ICU admissions. Mortality was independently associated with hemoptysis onset location, underlying diagnosis, and severity of critical illness at event. Additional mortality was observed in the 12-month posthospital discharge. Future directions include further characterization of this vulnerable population and management recommendations for life-threatening pediatric hemoptysis incorporating underlying disease pathophysiology., Competing Interests: Dr. Thiagarajan’s institution received funding from Bristol Myers Squibb and Pfizer. Dr. Alexander’s institution received funding from Novartis and Tenax Therapeutics (supplied therapeutic agent, levosimendan, at no charge to patients as part of a compassionate access clinical trial) and she disclosed off-label product use of extracorporeal membrane oxygenation and agents such as tranexamic acid, which are not U.S. Food and Drug Administration-approved for use in this population. 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.)

Ethical climate (EC) has been broadly described as how well institutions respond to ethical issues. Developing a tool to study and evaluate EC that aims to achieve sustained improvements requires a contemporary framework with identified relevant drivers. An extensive literature review was performed, reviewing existing EC definitions, tools and areas where EC has been studied; ethical challenges and relevance of EC in contemporary paediatric intensive care (PIC); and relevant ethical theories. We surmised that existing EC definitions and tools designed to measure it fail to capture nuances of the PIC environment, and sought to address existing gaps by developing an EC framework for PIC founded on ethical theory. In this article, we propose a Paediatric Intensive Care Ethical Climate (PICEC) conceptual framework and four measurable domains to be captured by an assessment tool. We define PICEC as the collective felt experience of interdisciplinary team members arising from those factors that enable or constrain their ability to navigate ethical aspects of their work. PICEC both results from and is influenced by how well ethical issues are understood, identified, explored, reflected on, responded to and addressed in the workplace. PICEC encompasses four, core inter-related domains representing drivers of EC including: (1) organisational culture and leadership; (2) interdisciplinary team relationships and dynamics; (3) integrated child and family-centred care; and (4) ethics literacy. Future directions involve developing a PICEC measurement tool, with implications for benchmarking as well as guidance for, and evaluation of, targeted interventions to foster a healthy EC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic β cells that are perturbed in Clock -/- and Bmal1 -/- β-cell lines. We show that the RNA-binding protein THRAP3 (thyroid hormone receptor-associated protein 3) regulates circadian clock-dependent AS by binding to exons at coding sequences flanking exons that are more frequently skipped in clock mutant β cells, including transcripts encoding Cask ( calcium/calmodulin-dependent serine protein kinase ) and Madd ( MAP kinase-activating death domain ). Depletion of THRAP3 restores expression of the long isoforms of Cask and Madd , and mimicking exon skipping in these transcripts through antisense oligonucleotide delivery in wild-type islets reduces glucose-stimulated insulin secretion. Finally, we identify shared networks of alternatively spliced exocytic genes from islets of rodent models of diet-induced obesity that significantly overlap with clock mutants. Our results establish a role for pre-mRNA alternative splicing in β-cell function across the sleep/wake cycle., (© 2020 Marcheva et al.; Published by Cold Spring Harbor Laboratory Press.)

Objectives: Viral infections are common in children, but there is a lack of data on severe viral infections in critically ill children. We investigated testing for viral infections in children requiring PICU admission and describe the epidemiology and outcomes., Design: Multicenter retrospective study. Results of viral testing for nine respiratory viruses using polymerase chain reaction were collected., Participants: Children less than 16 years old nonelectively admitted to PICU over a 6-year period., Setting: Two tertiary PICUs in Queensland, Australia., Interventions: None., Main Outcome Measures: Primary outcome was PICU length of stay. Secondary outcomes included need for and duration of intubation and mortality in PICU. Univariate and multivariate regression analyses were performed, adjusting for age, indigenous status, comorbidities, and severity of illness., Results: Of 6,426 nonelective admissions, 2,956 (46%) were polymerase chain reaction tested for a virus of which 1,353 (46%) were virus positive. Respiratory syncytial virus was the most common pathogen identified (n = 518, 33%), followed by rhinovirus/enterovirus and adenovirus. Across all patients who underwent polymerase chain reaction testing, identification of a respiratory virus was not significantly associated with longer overall length of stay (multivariate odds ratio, 1.08; 95% CI, 0.99-1.17; p = 0.068) or longer intubation (p = 0.181), whereas the adjusted odds for intubation and mortality were significantly lower (p < 0.01). Subgroup analyses restricted to patients with acute respiratory infections (n = 1,241), bronchiolitis (n = 761), pneumonia (n = 311), confirmed bacterial infection (n = 345), and malignancy (n = 95) showed that patients positive for a virus on testing had significantly longer PICU length of stay (multivariate p < 0.05). In children with pneumonia, identification of a respiratory virus was associated with significantly increased duration of ventilation (p = 0.003). No association between positive test results for multiple viruses and outcomes was observed., Conclusion: Viral infections are common in critically ill children. Viral infections were associated with lower intubation and mortality rates compared with all children testing negative for viral infections. In several subgroups studied, identification of viral pathogens was associated with longer PICU length of stay while mortality was comparable. Prospective studies are required to determine the benefit of routine testing for respiratory viruses at the time of PICU admission.

Purpose: Data on childhood intensive care unit (ICU) deaths are needed to identify changing patterns of intensive care resource utilization. We sought to determine the epidemiology and mode of pediatric ICU deaths in Australia and New Zealand (ANZ)., Methods: This was a retrospective, descriptive study of multicenter data from pediatric and mixed ICUs reported to the ANZ Pediatric Intensive Care Registry and binational Government census. All patients < 16 years admitted to an ICU between 1 January 2006 and 31 December 2016 were included. Primary outcome was ICU mortality. Subject characteristics and trends over time were evaluated., Results: Of 103,367 ICU admissions, there were 2672 (2.6%) deaths, with 87.6% of deaths occurring in specialized pediatric ICUs. The proportion of ANZ childhood deaths occurring in ICU was 12%, increasing by 43% over the study period. Unadjusted (0.1% per year, 95% CI 0.096-0.104; p < 0.001) and risk-adjusted (0.1%/year, 95% CI 0.07-0.13; p < 0.001) ICU mortality rates fell. Across all admission sources and diagnostic groups, mortality declined except following pre-ICU cardiopulmonary arrest where increased mortality was observed. Half of the deaths followed withdrawal of life-sustaining therapy (51%), remaining constant throughout the study. Deaths despite maximal resuscitation declined (0.92%/year, 95% CI 0.89-0.95%; p < 0.001) and brain death diagnoses increased (0.72%/year, 95% CI 0.69-0.75%; p = 0.001)., Conclusions: Unadjusted and risk-adjusted mortality for children admitted to ANZ ICUs is declining. Half of pediatric ICU deaths follow withdrawal of life-sustaining therapy. Epidemiology and mode of pediatric ICU death are changing. Further investigation at an international level will inform benchmarking, resource allocation and training requirements for pediatric critical care.

Integration of pediatric palliative care (PPC) into management of children with serious illness and their families is endorsed as the standard of care. Despite this, timely referral to and integration of PPC into the traditionally cure-oriented cardiac ICU (CICU) remains variable. Despite dramatic declines in mortality in pediatric cardiac disease, key challenges confront the CICU community. Given increasing comorbidities, technological dependence, lengthy recurrent hospitalizations, and interventions risking significant morbidity, many patients in the CICU would benefit from PPC involvement across the illness trajectory. Current PPC delivery models have inherent disadvantages, insufficiently address the unique aspects of the CICU setting, place significant burden on subspecialty PPC teams, and fail to use CICU clinician skill sets. We therefore propose a novel conceptual framework for PPC-CICU integration based on literature review and expert interdisciplinary, multi-institutional consensus-building. This model uses interdisciplinary CICU-based champions who receive additional PPC training through courses and subspecialty rotations. PPC champions strengthen CICU PPC provision by (1) leading PPC-specific educational training of CICU staff; (2) liaising between CICU and PPC, improving use of support staff and encouraging earlier subspecialty PPC involvement in complex patients' management; and (3) developing and implementing quality improvement initiatives and CICU-specific PPC protocols. Our PPC-CICU integration model is designed for adaptability within institutional, cultural, financial, and logistic constraints, with potential applications in other pediatric settings, including ICUs. Although the PPC champion framework offers several unique advantages, barriers to implementation are anticipated and additional research is needed to investigate the model's feasibility, acceptability, and efficacy., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

The alignment of fasting and feeding with the sleep/wake cycle is coordinated by hypothalamic neurons, though the underlying molecular programs remain incompletely understood. Here, we demonstrate that the clock transcription pathway maximizes eating during wakefulness and glucose production during sleep through autonomous circadian regulation of NPY/AgRP neurons. Tandem profiling of whole-cell and ribosome-bound mRNAs in morning and evening under dynamic fasting and fed conditions identified temporal control of activity-dependent gene repertoires in AgRP neurons central to synaptogenesis, bioenergetics, and neurotransmitter and peptidergic signaling. Synaptic and circadian pathways were specific to whole-cell RNA analyses, while bioenergetic pathways were selectively enriched in the ribosome-bound transcriptome. Finally, we demonstrate that the AgRP clock mediates the transcriptional response to leptin. Our results reveal that time-of-day restriction in transcriptional control of energy-sensing neurons underlies the alignment of hunger and food acquisition with the sleep/wake state., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Reduction of nosocomial infections represents an increasingly recognized aspect of PICU benchmarking. We investigated the prevalence and outcomes of viral respiratory infections acquired during admission to PICU., Design: Multicenter, statewide retrospective linkage study., Setting: Tertiary PICU., Patients: All children less than 16 years requiring PICU admission for greater than 48 hours from January 1, 2008, until December 31, 2013., Intervention: Testing was performed in symptomatic patients using an extended panel polymerase chain reaction capturing nine respiratory viruses. Duration of intubation and total duration of respiratory support were primary outcomes., Measurements and Main Results: Of 3,607 patients admitted to PICU for greater than 48 hours, 102 (2.8%) were diagnosed with a PICU-associated viral infection out of 702 patients (19.4%) undergoing viral testing, reflecting a rate of 2.8 PICU-associated viral infections per 1,000 PICU patient days. Compared with negative/untested patients, those with PICU-associated viral infections had greater intubation duration (median 164 vs 67; p< 0.001), longer respiratory support (204 vs 68 hr; p < 0.001), were more likely to require extracorporeal life support (odds ratio, 5.3; 2.7-10.3; p < 0.001), high-frequency oscillatory ventilation (odds ratio, 3.0; 1.7-5.4; p < 0.001), and inhaled nitric oxide (odds ratio, 2.7; 1.5-5.0; p = 0.001). When comparing patients with PICU-associated viral infection with patients who tested negative for respiratory viruses, no substantial difference in these outcomes was found., Conclusions: The acquisition of viral infections during PICU admission is less frequent compared with previous reports on bacterial and fungal hospital-acquired infections. We did not observe worse patient-centered outcomes when comparing virus positive versus tested but negative patients. Our findings challenge the clinical value of performing viral respiratory diagnostics in PICU patients evaluated for infection.

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia and may cause life-threatening disease in children. We identified 30 (0.3%) confirmed M. pneumoniae cases by clinical and laboratory criteria in 11,526 pediatric intensive care unit admissions. Outcomes were comparable to patients admitted with other infections (n=3005; P > 0.1). Our findings indicate that empiric antimicrobial coverage for M. pneumoniae infection in pediatric intensive care unit is rarely needed.

The mammalian circadian clock is encoded by an autoregulatory transcription feedback loop that drives rhythmic behavior and gene expression in the brain and peripheral tissues. Transcriptomic analyses indicate cell type-specific effects of circadian cycles on rhythmic physiology, although how clock cycles respond to environmental stimuli remains incompletely understood. Here, we show that activation of the inducible transcription factor NF-κB in response to inflammatory stimuli leads to marked inhibition of clock repressors, including the Period , Cryptochrome , and Rev-erb genes, within the negative limb. Furthermore, activation of NF-κB relocalizes the clock components CLOCK/BMAL1 genome-wide to sites convergent with those bound by NF-κB, marked by acetylated H3K27, and enriched in RNA polymerase II. Abrogation of NF-κB during adulthood alters the expression of clock repressors, disrupts clock-controlled gene cycles, and impairs rhythmic activity behavior, revealing a role for NF-κB in both unstimulated and activated conditions. Together, these data highlight NF-κB-mediated transcriptional repression of the clock feedback limb as a cause of circadian disruption in response to inflammation., (© 2018 Hong et al.; Published by Cold Spring Harbor Laboratory Press.)

The Declaration of Geneva was recently revised to emphasize patient autonomy and the importance of clinicians sharing medical knowledge. This reflects the welcome evolution of the doctor-patient relationship from one of paternalism to more informed, shared decision-making. Unfortunately, there is an increasing trend for clinicians to avoid making recommendations, instead providing a "menu" of care options from which patients and families must choose. This seems to be underpinned by the belief that it is unacceptably paternalistic to give guidance as to which course of action may be best to take. In this article, we argue that there is an ethical imperative for doctors to provide medical recommendations. This is discussed with particular emphasis on the pediatric critical care setting, where autonomy and shared decision-making are especially complex. We outline how a failure to provide clinical recommendations represents inadequate shared decision-making and erodes the doctor-patient relationship, leading to suboptimal care, paradoxically decreasing respect for autonomy. We describe an approach through which doctors can avoid paternalism without placing an undue burden of decision-making on families. We assert that patients' interests are best served by clinicians taking an active, relational role in shared decision-making, including exploration of values and giving explicit medical recommendations for care.

Each spring, we get out of bed 1 h ahead of our biological wake-up time due to the misalignment of internal clocks with the light-dark cycle. Genetic discoveries revealed that clock genes encode transcription factors that are expressed throughout many tissues, yet a gap has remained in understanding the temporal dynamics of transcription. Two groups now apply circular chromosome conformation capture and high-throughput sequencing to dissect how "time of day"-dependent changes in chromatin drive core clock oscillations. A surprise is the finding that disruption of enhancer-promoter contacts within chromatin leads to an advance in the "wake-up" time of mice. Furthermore, the assembly of transcriptionally active domains of chromatin requires the ordered recruitment of core clock transcription factors each day. These studies show that waking up involves highly dynamic changes in the three-dimensional positioning of genes within the cell., (© 2018 Weidemann et al.; Published by Cold Spring Harbor Laboratory Press.)

Circadian clocks are encoded by a transcription-translation feedback loop that aligns energetic processes with the solar cycle. We show that genetic disruption of the clock activator BMAL1 in skeletal myotubes and fibroblasts increased levels of the hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions. Bmal1 -/- myotubes displayed reduced anaerobic glycolysis, mitochondrial respiration with glycolytic fuel, and transcription of HIF1α targets Phd3, Vegfa, Mct4, Pk-m, and Ldha, whereas abrogation of the clock repressors CRY1/2 stabilized HIF1α in response to hypoxia. HIF1α bound directly to core clock gene promoters, and, when co-expressed with BMAL1, led to transactivation of PER2-LUC and HRE-LUC reporters. Further, genetic stabilization of HIF1α in Vhl -/- cells altered circadian transcription. Finally, induction of clock and HIF1α target genes in response to strenuous exercise varied according to the time of day in wild-type mice. Collectively, our results reveal bidirectional interactions between circadian and HIF pathways that influence metabolic adaptation to hypoxia., (Copyright © 2017 Elsevier Inc. All rights reserved.)