Advocate Children's Hospital

OBJECTIVES: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction. DESIGN: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process. METHODS: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 52 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 49 research priorities were identified. CONCLUSIONS: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.

OBJECTIVE: This update of a 2011 guideline developed by the American Academy of Otolaryngology-Head and Neck Surgery Foundation provides evidence-based recommendations on the pre-, intra-, and postoperative care and management of children 1 to 18 years of age under consideration for tonsillectomy. Tonsillectomy is defined as a surgical procedure performed with or without adenoidectomy that completely removes the tonsil, including its capsule, by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. Tonsillectomy is one of the most common surgical procedures in the United States, with 289,000 ambulatory procedures performed annually in children <15 years of age based on the most recent published data. This guideline is intended for all clinicians in any setting who interact with children who may be candidates for tonsillectomy. PURPOSE: The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing children under consideration for tonsillectomy and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to educate clinicians, patients, and/or caregivers regarding the indications for tonsillectomy and the natural history of recurrent throat infections. Additional goals include the following: optimizing the perioperative management of children undergoing tonsillectomy, emphasizing the need for evaluation and intervention in special populations, improving the counseling and education of families who are considering tonsillectomy for their children, highlighting the management options for patients with modifying factors, and reducing inappropriate or unnecessary variations in care. Children aged 1 to 18 years under consideration for tonsillectomy are the target patient for the guideline. For this guideline update, the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of nursing, anesthesiology, consumers, family medicine, infectious disease, otolaryngology-head and neck surgery, pediatrics, and sleep medicine. KEY ACTION STATEMENTS: The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should recommend watchful waiting for recurrent throat infection if there have been <7 episodes in the past year, <5 episodes per year in the past 2 years, or <3 episodes per year in the past 3 years. (2) Clinicians should administer a single intraoperative dose of intravenous dexamethasone to children undergoing tonsillectomy. (3) Clinicians should recommend ibuprofen, acetaminophen, or both for pain control after tonsillectomy. The guideline update group made recommendations for the following KASs: (1) Clinicians should assess the child with recurrent throat infection who does not meet criteria in KAS 2 for modifying factors that may nonetheless favor tonsillectomy, which may include but are not limited to multiple antibiotic allergies/intolerance, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis), or history of >1 peritonsillar abscess. (2) Clinicians should ask caregivers of children with obstructive sleep-disordered breathing and tonsillar hypertrophy about comorbid conditions that may improve after tonsillectomy, including growth retardation, poor school performance, enuresis, asthma, and behavioral problems. (3) Before performing tonsillectomy, the clinician should refer children with obstructive sleep-disordered breathing for polysomnography if they are <2 years of age or if they exhibit any of the following: obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (4) The clinician should advocate for polysomnography prior to tonsillectomy for obstructive sleep-disordered breathing in children without any of the comorbidities listed in KAS 5 for whom the need for tonsillectomy is uncertain or when there is discordance between the physical examination and the reported severity of oSDB. (5) Clinicians should recommend tonsillectomy for children with obstructive sleep apnea documented by overnight polysomnography. (6) Clinicians should counsel patients and caregivers and explain that obstructive sleep-disordered breathing may persist or recur after tonsillectomy and may require further management. (7) The clinician should counsel patients and caregivers regarding the importance of managing posttonsillectomy pain as part of the perioperative education process and should reinforce this counseling at the time of surgery with reminders about the need to anticipate, reassess, and adequately treat pain after surgery. (8) Clinicians should arrange for overnight, inpatient monitoring of children after tonsillectomy if they are <3 years old or have severe obstructive sleep apnea (apnea-hypopnea index ≥10 obstructive events/hour, oxygen saturation nadir <80%, or both). (9) Clinicians should follow up with patients and/or caregivers after tonsillectomy and document in the medical record the presence or absence of bleeding within 24 hours of surgery (primary bleeding) and bleeding occurring later than 24 hours after surgery (secondary bleeding). (10) Clinicians should determine their rate of primary and secondary posttonsillectomy bleeding at least annually. The guideline update group made a strong recommendation against 2 actions: (1) Clinicians should not administer or prescribe perioperative antibiotics to children undergoing tonsillectomy. (2) Clinicians must not administer or prescribe codeine, or any medication containing codeine, after tonsillectomy in children younger than 12 years. The policy level for the recommendation about documenting recurrent throat infection was an option: (1) Clinicians may recommend tonsillectomy for recurrent throat infection with a frequency of at least 7 episodes in the past year, at least 5 episodes per year for 2 years, or at least 3 episodes per year for 3 years with documentation in the medical record for each episode of sore throat and ≥1 of the following: temperature >38.3°C (101°F), cervical adenopathy, tonsillar exudate, or positive test for group A beta-hemolytic streptococcus. DIFFERENCES FROM PRIOR GUIDELINE: (1) Incorporating new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply. (2) There were 1 new clinical practice guideline, 26 new systematic reviews, and 13 new randomized controlled trials included in the current guideline update. (3) Inclusion of 2 consumer advocates on the guideline update group. (4) Changes to 5 KASs from the original guideline: KAS 1 (Watchful waiting for recurrent throat infection), KAS 3 (Tonsillectomy for recurrent infection with modifying factors), KAS 4 (Tonsillectomy for obstructive sleep-disordered breathing), KAS 9 (Perioperative pain counseling), and KAS 10 (Perioperative antibiotics). (5) Seven new KASs: KAS 5 (Indications for polysomnography), KAS 6 (Additional recommendations for polysomnography), KAS 7 (Tonsillectomy for obstructive sleep apnea), KAS 12 (Inpatient monitoring for children after tonsillectomy), KAS 13 (Postoperative ibuprofen and acetaminophen), KAS 14 (Postoperative codeine), and KAS 15a (Outcome assessment for bleeding). (6) Addition of an algorithm outlining KASs. (7) Enhanced emphasis on patient and/or caregiver education and shared decision making.

The hypermobile type of Ehlers-Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue. It has been described largely in those with musculoskeletal complaints including joint hypermobility, joint subluxations/dislocations, as well as skin and soft tissue manifestations. Many patients report activity-related pain and some go on to have daily pain. Two undifferentiated syndromes have been used to describe these manifestations-joint hypermobility syndrome and hEDS. Both are clinical diagnoses in the absence of other causation. Current medical literature further complicates differentiation and describes multiple associated symptoms and disorders. The current EDS nosology combines these two entities into the hypermobile type of EDS. Herein, we review and summarize the literature as a better clinical description of this type of connective tissue disorder. © 2017 Wiley Periodicals, Inc.

OBJECTIVE: This update of a 2011 guideline developed by the American Academy of Otolaryngology-Head and Neck Surgery Foundation provides evidence-based recommendations on the pre-, intra-, and postoperative care and management of children 1 to 18 years of age under consideration for tonsillectomy. Tonsillectomy is defined as a surgical procedure performed with or without adenoidectomy that completely removes the tonsil, including its capsule, by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. Tonsillectomy is one of the most common surgical procedures in the United States, with 289,000 ambulatory procedures performed annually in children <15 years of age, based on the most recent published data. This guideline is intended for all clinicians in any setting who interact with children who may be candidates for tonsillectomy. PURPOSE: The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing children under consideration for tonsillectomy and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to educate clinicians, patients, and/or caregivers regarding the indications for tonsillectomy and the natural history of recurrent throat infections. Additional goals include the following: optimizing the perioperative management of children undergoing tonsillectomy, emphasizing the need for evaluation and intervention in special populations, improving the counseling and education of families who are considering tonsillectomy for their children, highlighting the management options for patients with modifying factors, and reducing inappropriate or unnecessary variations in care. Children aged 1 to 18 years under consideration for tonsillectomy are the target patient for the guideline. For this guideline update, the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of nursing, anesthesiology, consumers, family medicine, infectious disease, otolaryngology-head and neck surgery, pediatrics, and sleep medicine. KEY ACTION STATEMENTS: The guideline update group made strong recommendations for the following key action statements (KASs): (1) Clinicians should recommend watchful waiting for recurrent throat infection if there have been <7 episodes in the past year, <5 episodes per year in the past 2 years, or <3 episodes per year in the past 3 years. (2) Clinicians should administer a single intraoperative dose of intravenous dexamethasone to children undergoing tonsillectomy. (3) Clinicians should recommend ibuprofen, acetaminophen, or both for pain control after tonsillectomy. The guideline update group made recommendations for the following KASs: (1) Clinicians should assess the child with recurrent throat infection who does not meet criteria in KAS 2 for modifying factors that may nonetheless favor tonsillectomy, which may include but are not limited to multiple antibiotic allergies/intolerance, PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis), or history of >1 peritonsillar abscess. (2) Clinicians should ask caregivers of children with obstructive sleep-disordered breathing and tonsillar hypertrophy about comorbid conditions that may improve after tonsillectomy, including growth retardation, poor school performance, enuresis, asthma, and behavioral problems. (3) Before performing tonsillectomy, the clinician should refer children with obstructive sleep-disordered breathing for polysomnography if they are <2 years of age or if they exhibit any of the following: obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (4) The clinician should advocate for polysomnography prior to tonsillectomy for obstructive sleep-disordered breathing in children without any of the comorbidities listed in KAS 5 for whom the need for tonsillectomy is uncertain or when there is discordance between the physical examination and the reported severity of obstructive sleep-disordered breathing. (5) Clinicians should recommend tonsillectomy for children with obstructive sleep apnea documented by overnight polysomnography. (6) Clinicians should counsel patients and caregivers and explain that obstructive sleep-disordered breathing may persist or recur after tonsillectomy and may require further management. (7) The clinician should counsel patients and caregivers regarding the importance of managing posttonsillectomy pain as part of the perioperative education process and should reinforce this counseling at the time of surgery with reminders about the need to anticipate, reassess, and adequately treat pain after surgery. (8) Clinicians should arrange for overnight, inpatient monitoring of children after tonsillectomy if they are <3 years old or have severe obstructive sleep apnea (apnea-hypopnea index ≥10 obstructive events/hour, oxygen saturation nadir <80%, or both). (9) Clinicians should follow up with patients and/or caregivers after tonsillectomy and document in the medical record the presence or absence of bleeding within 24 hours of surgery (primary bleeding) and bleeding occurring later than 24 hours after surgery (secondary bleeding). (10) Clinicians should determine their rate of primary and secondary posttonsillectomy bleeding at least annually. The guideline update group made a strong recommendation against 2 actions: (1) Clinicians should not administer or prescribe perioperative antibiotics to children undergoing tonsillectomy. (2) Clinicians must not administer or prescribe codeine, or any medication containing codeine, after tonsillectomy in children younger than 12 years. The policy level for the recommendation about documenting recurrent throat infection was an option: (1) Clinicians may recommend tonsillectomy for recurrent throat infection with a frequency of at least 7 episodes in the past year, at least 5 episodes per year for 2 years, or at least 3 episodes per year for 3 years with documentation in the medical record for each episode of sore throat and ≥1 of the following: temperature >38.3°C (101°F), cervical adenopathy, tonsillar exudate, or positive test for group A beta-hemolytic streptococcus. DIFFERENCES FROM PRIOR GUIDELINE: Incorporating new evidence profiles to include the role of patient preferences, confidence in the evidence, differences of opinion, quality improvement opportunities, and any exclusion to which the action statement does not apply. There were 1 new clinical practice guideline, 26 new systematic reviews, and 13 new randomized controlled trials included in the current guideline update. Inclusion of 2 consumer advocates on the guideline update group. Changes to 5 KASs from the original guideline: KAS 1 (Watchful waiting for recurrent throat infection), KAS 3 (Tonsillectomy for recurrent infection with modifying factors), KAS 4 (Tonsillectomy for obstructive sleep-disordered breathing), KAS 9 (Perioperative pain counseling), and KAS 10 (Perioperative antibiotics). Seven new KASs: KAS 5 (Indications for polysomnography), KAS 6 (Additional recommendations for polysomnography), KAS 7 (Tonsillectomy for obstructive sleep apnea), KAS 12 (Inpatient monitoring for children after tonsillectomy), KAS 13 (Postoperative ibuprofen and acetaminophen), KAS 14 (Postoperative codeine), and KAS 15a (Outcome assessment for bleeding). Addition of an algorithm outlining KASs. Enhanced emphasis on patient and/or caregiver education and shared decision making.

BACKGROUND: encephalopathy and explored potential prospects of personalised medicine. METHODS: variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)-approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

In 2001, the Surviving Sepsis Campaign (SSC) began to develop evidence-based guidelines and recommendations for the resuscitation and management of patients with sepsis. With the 2016 edition, the Society of Critical Care Medicine and European Society of Intensive Care Medicine recommended a separate task force be dedicated to guideline formulation for children. The objective of the “Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children” is to provide guidance for the care of infants, children, and adolescents with septic shock and other sepsis-associated organ dysfunction. Recommendations are intended to guide “best practice” rather than to establish a treatment algorithm or to define standard of care and cannot replace the clinician’s decision-making capability when presented with a patient’s unique set of clinical variables. METHODS This executive summary briefly reviews the methodology, with additional details provided in the complete guidelines document published in Pediatric Critical Care Medicine and Intensive Care Medicine. Definitions For these guidelines, we defined “septic shock” in children as severe infection leading to cardiovascular dysfunction (including hypotension, need for treatment with a vasoactive medication, or impaired perfusion) and “sepsis-associated organ dysfunction” in children as severe infection leading to cardiovascular and/or noncardiovascular organ dysfunction. These definitions include the criteria set forth by the 2005 International Pediatric Sepsis Consensus Conference (1), as the majority of studies used to establish evidence for these guidelines referred to this nomenclature. However, studies that defined sepsis in children as severe infection leading to life-threatening organ dysfunction were included even if criteria used to define sepsis deviated from the 2005 consensus definitions. Because several methods to identify acute organ dysfunction in children are currently available, we did not to require a specific definition or scheme for this purpose. Scope of Patients The panel intended these guidelines to apply to all patients from greater than or equal to 37 weeks gestation at birth to 18 years with septic shock or other sepsis-associated acute organ dysfunction. Practically, all infants, children, and adolescents with septic shock or other sepsis-associated organ dysfunction are included in this scope. For simplicity, we used the term “children” to refer to infants, school-aged children, and adolescents in these guidelines. All recommendations apply to children with septic shock and other sepsis-associated acute organ dysfunction unless specific qualifications, such as the subset with immune compromise, are included in the recommendation. Even though these guidelines are not intended to address the management of infection with or without systemic inflammatory response syndrome when there is not associated acute organ dysfunction, we recognize that sepsis exists as a spectrum and some children without known acute organ dysfunction may still benefit from similar therapies as those with known organ dysfunction. Finally, acknowledging that neonatal sepsis, especially in premature babies, may have distinct pathology, biology, and therapeutic considerations, newborns less than 37 weeks gestation are excluded from the scope of these guidelines. The panel sought to include term neonates (0–28 d) born at greater than or equal to 37 weeks gestation within the scope of these guidelines because these infants may be recognized and resuscitated outside of a newborn nursery or neonatal ICU. However, because the panel did not specifically address studies of neonates with perinatal infection or all conditions that can be associated with neonatal sepsis (e.g., persistent pulmonary hypertension of the newborn), these guidelines do not address all management considerations for neonatal sepsis. Application of Guidelines by Local Resource Availability The intended users of these guidelines are health professionals caring for children in a hospital, emergency, or other acute care setting. However, many of the recommendations are likely to apply to the care of children in other settings and will need to be adapted to specific environments and resource availability. In addition, these guidelines were largely developed without consideration of the availability of healthcare services, although we realize that medical care is necessarily carried out within the confines of locally available resources. The panel supports that these guidelines should constitute a general scheme of “best practice,” but that translation of these guidelines to treatment algorithms or bundles and standards of care will need to account for variation in the availability of local healthcare resources, particularly in resource-limited settings. Selection and Organization of Panel Members The selection of panel members was based on their expertise in specific aspects of pediatric sepsis, with broad international and multi-professional representation from diverse geographic settings and healthcare systems. Three members from the lay public were also included. Panelists were divided into the following subgroups: 1) recognition and management of infection, 2) hemodynamics and resuscitation, 3) ventilation, 4) endocrine and metabolic therapies, and 5) adjunctive therapies. A sixth subgroup reviewed research priorities. Each subgroup was supported by a trained methodologist. Question Development and Outcome Prioritization The panel selected topics addressed in the 2016 adult SSC guidelines that were relevant to children, as well as other key topics important to children with sepsis. The PICO format, which describes the population (P), intervention (I), control (C), and outcomes (O), was used for all guideline questions. For practical reasons, we excluded several issues pertaining to general acute or critical illness that were not specific for sepsis (e.g., head-of-bed positioning during invasive mechanical ventilation) and have been addressed in other guidelines (e.g., Pediatric Acute Lung Injury Consensus Conference) (2). However, topics with particular relevance to children with septic shock or other sepsis-associated acute organ dysfunction were included in this guideline, even if there was evaluation of similar or overlapping topics in previous publications. The final list of PICO questions is provided as Supplemental Table 1 (Supplemental Digital Content 1, https://links.lww.com/PCC/B139) in the complete guidelines. Search Strategy and Evidence Summation Professional medical librarians assisted with the literature searches and utilized a combination of controlled vocabulary (e.g., “sepsis,” “bacterial infections,” “critical illness,” “intensive care units,” “pediatrics,” “NICU,” “PICU,” “emergency service”), key words (e.g., “toxic shock,” “blood poisoning,” “acute infection,” “child”), and qualifiers specific to each PICO question. Only English language studies were included. As this was the inaugural version of these guidelines for children, all publications through May 1, 2017, were considered. Key studies published after the conclusion of the initial literature search were incorporated into the evidence synthesis if identified by panel members as important and relevant even if they were not part of the initial literature review. Formulation of Recommendations The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) principles guided the assessment of quality of evidence from high to very low and were used to determine the strength of recommendations. The GRADE approach to assess the quality of evidence is based on the evaluation of six domains: 1) risk of bias, 2) inconsistency, 3) indirectness, 4) imprecision, 5) publication bias, and 6) assessment of the balance between benefit and harm, patients’ values and preferences, cost and resources, and feasibility and acceptability of the intervention (3). The panel initially considered research focused on pediatric patients using the following hierarchy of evidence: systematic reviews, randomized controlled trials, prospective observational studies, retrospective observational studies, case-control studies, and large case series. Research focusing on children with septic shock and other sepsis-associated organ dysfunction was prioritized, although studies inclusive of more general pediatric populations (e.g., all PICU patients) were considered for some questions on a case-by-case basis. If there were insufficient data in children with sepsis or general pediatric illness, data from adult studies were considered using a pre-specified framework to guide appropriateness of indirect evidence. Each of the subgroups used the Evidence-to-Decision (EtD) framework to facilitate transition from evidence to recommendations. The EtD framework ensured that panel members took into consideration not only the quality of evidence and magnitude of effect, but also balance between benefits and harms, patients’ values and preferences, resources, cost, acceptability, and feasibility (4). We classified recommendations as strong or weak using the language “We recommend…” or “We suggest…,” respectively. We judged a strong recommendation in favor of an intervention to have desirable effects of adherence that will clearly outweigh the undesirable effects. The implications of calling a recommendation strong are that most patients would accept that intervention and that most clinicians should use it in most situations. However, a strong recommendation does not imply a standard of care, and circumstances may exist in which a strong recommendation cannot or should not be followed for an individual patient. We judged a weak recommendation in favor of an intervention to have desirable consequences of adherence that will probably outweigh the undesirable consequences, but confidence is diminished either because the quality of evidence was low or the benefits and risks were closely balanced. We anticipate that a weak recommendation, while still relevant for most patients in most settings, will be more heavily influenced by clinical circumstances and patients’ values than a strong recommendation. We permitted strong recommendations “for” an intervention based on low or very low quality of evidence when the intervention had the potential to improve survival and there was low risk for immediate harm. We permitted strong recommendations “against” an intervention based on low or very low quality of evidence when there was uncertain benefit but very likely or certain harm, including high costs (5). Best practice statements (BPSs) were offered when the evidence could not be summarized using GRADE methodology but the benefit or harm was deemed unequivocal. In addition, when evidence was insufficient to make a recommendation, but the panel felt that some guidance may be appropriate, we issued an “in our practice” statement. The “in our practice” statements were developed through a survey of panelists to ascertain their state of current practice in an attempt to describe current variation in care. “In our practice” statements, therefore, should not be construed as recommendations. Voting Process Panel members convened to review evidence and discuss recommendations in-person and through web conferences. Panelists then indicated agreement or disagreement (or abstention if conflict of interest present) with each recommendation. Up to three rounds of voting were conducted in an attempt to achieve consensus. Acceptance of a statement required votes from 75% of panel members with an 80% agreement threshold. Conflict of Interest Policy Conflict-of-interest disclosures were sought from all panelists prior to commencing activities, with updates annually and as needed. There was no industry input into or support of the guideline development process. Only librarians and a supporting project manager received compensation for their work. RECOMMENDATIONS The consensus recommendations of the “Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-associated Organ Dysfunction in Children” are summarized in Table 1 of this executive summary. The rationale and evidence profiles supporting each recommendations are presented in the complete guidelines (6). The panel issued 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction, including six strong recommendations, 49 weak recommendations, and nine BPSs. For 13 questions, no recommendations could be made, but, for 10 of these, “in our practice” statements were provided. In addition, 52 knowledge gaps and research opportunities were identified (see complete guidelines).TABLE 1.: Executive Summary of GuidelinesCONCLUSIONS Although most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations, these guidelines regarding the management of children with septic shock and other sepsis-associated organ dysfunction should provide a foundation for consistent care to improve outcomes and inform future research.

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

In just over 100 years, surgical education in the United States has evolved from a disorganized practice to a refined system esteemed worldwide as one of the premier models for the training of physicians and surgeons. But in the changing environment of health care, new challenges have arisen that could warrant a reform. To design our future, we must understand our past. The present work is not intended to be a comprehensive account of the history of American surgery. Instead, it tells the abridged history of surgical education in our country: the evolution from apprenticeships to residencies; the birth of hospital-based teaching; the impact of key historical events on training; the marks left by some preeminent characters; the conception of regulatory entities that steer our education; and, finally, how our process of training surgeons might need to be refined for the continued progress of our profession. Told in chronological order in a manner that will be memorable to readers, this story weaves together the key events that explain how our current surgical training models came to be. We conclude with a timely invitation to draw from these past lessons to redesign the future of graduate medical education, making a case for the transition to time-variable, competency-based medical education for surgical residency programs in America.

Anemia is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). It can be asymptomatic or associated with nonspecific symptoms, such as irritability, headaches, fatigue, dizziness, and anorexia. In IBD patients, the etiology of anemia is often multifactorial. Various causes include iron deficiency, anemia of inflammation and chronic disease, vitamin deficiencies, hemolysis, or myelosuppressive effect of drugs. Anemia and iron deficiency in these patients may be underestimated because of their insidious onset, lack of standardized screening practices, and possibly underappreciation that treatment of anemia is also required when treating IBD. Practitioners may hesitate to use oral preparations because of their intolerance whereas intravenous preparations are underutilized because of fear of adverse events, availability, and cost. Several publications in recent years have documented the safety and comparative efficacy of various intravenous preparations. This article reviews management of anemia in children with IBD, including diagnosis, etiopathogenesis, evaluation of a patient, protocol to screen and monitor patients for early detection and response to therapy, treatment including parenteral iron therapy, and newer approaches in management of anemia of chronic disease. This report has been compiled by a group of pediatric gastroenterologists serving on the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) IBD committee, in collaboration with a pediatric hematologist, pharmacist, and a registered dietician who specializes in pediatric IBD (IBD Anemia Working Group), after an extensive review of the current literature. The purpose of this review is to raise awareness of under-diagnosis of anemia in children with IBD and make recommendations for screening, testing, and treatment in this population.

Pediatric sepsis is a major public health problem. Published treatment guidelines and several initiatives have increased adherence with guideline recommendations and have improved patient outcomes, but the gains are modest, and persistent gaps remain. The Children's Hospital Association Improving Pediatric Sepsis Outcomes (IPSO) collaborative seeks to improve sepsis outcomes in pediatric emergency departments, ICUs, general care units, and hematology/oncology units. We developed a multicenter quality improvement learning collaborative of US children's hospitals. We reviewed treatment guidelines and literature through 2 in-person meetings and multiple conference calls. We defined and analyzed baseline sepsis-attributable mortality and hospital-onset sepsis and developed a key driver diagram (KDD) on the basis of treatment guidelines, available evidence, and expert opinion. Fifty-six hospital-based teams are participating in IPSO; 100% of teams are engaged in educational and information-sharing activities. A baseline, sepsis-attributable mortality of 3.1% was determined, and the incidence of hospital-onset sepsis was 1.3 cases per 1000 hospital admissions. A KDD was developed with the aim of reducing both the sepsis-attributable mortality and the incidence of hospital-onset sepsis in children by 25% from baseline by December 2020. To accomplish these aims, the KDD primary drivers focus on improving the following: treatment of infection; recognition, diagnosis, and treatment of sepsis; de-escalation of unnecessary care; engagement of patients and families; and methods to optimize performance. IPSO aims to improve sepsis outcomes through collaborative learning and reliable implementation of evidence-based interventions.

Importance: In 2022, the US House of Representatives passed a bipartisan resolution (House of Representatives Resolution 1118 at the 117th Congress [2021-2022]) calling for meaningful nutrition education for medical trainees. This was prompted by increasing health care spending attributed to the growing prevalence of nutrition-related diseases and the substantial federal funding via Medicare that supports graduate medical education. In March 2023, medical education professional organizations agreed to identify nutrition competencies for medical education. Objective: To recommend nutrition competencies for inclusion in medical education to improve patient and population health. Evidence Review: The research team conducted a rapid literature review to identify existing nutrition-related competencies published between July 2013 and July 2023. Additional competencies were identified from learning objectives in selected nutrition, culinary medicine, and teaching kitchen curricula; dietetic core competencies; and research team-generated de novo competencies. An expert panel of 22 nutrition subject matter experts and 15 residency program directors participated in a modified Delphi process and completed 4 rounds of voting to reach consensus on recommended nutrition competencies, the level of medical education at which they should be included, and recommendations for monitoring implementation and evaluation of these competencies. Findings: A total of 15 articles met inclusion criteria for competency extraction and yielded 187 competencies. Through review of gray literature and other sources, researchers identified 167 additional competencies for a total of 354 competencies. These competencies were compiled and refined prior to voting. After 4 rounds of voting, 36 competencies were identified for recommendation: 30 at both undergraduate and graduate levels, 2 at the undergraduate level only, and 4 at the graduate level only. Competencies fell into the following nutrition-related themes: foundational nutrition knowledge, assessment and diagnosis, communication skills, public health, collaborative support and treatment for specific conditions, and indications for referral. A total of 36 panelists (97%) recommended nutrition competencies be assessed as part of licensing and board certification examinations. Conclusions and Relevance: These competencies represent a US-based effort to use a modified Delphi process to establish consensus on nutrition competencies for medical students and physician trainees. These competencies will require an iterative process of institutional prioritization, refinement, and inclusion in current and future educational curricula as well as licensure and certification examinations.

BACKGROUND: Rare de novo mutations have been implicated as a significant cause of idiopathic intellectual disability. Large deletions encompassing 10p11.23 have been implicated in developmental delay, behavioural abnormalities and dysmorphic features, but the genotype-phenotype correlation was not delineated. Mutations in WAC have been recently reported in large screening cohorts of patients with intellectual disability or autism, but no full phenotypic characterisation was described. METHODS: Clinical and molecular characterisation of six patients with loss-of-function WAC mutations identified by whole exome sequencing was performed. Clinical data were obtained by retrospective chart review, parental interviews, direct patient interaction and formal neuropsychological evaluation. RESULTS: Five heterozygous de novo WAC mutations were identified in six patients. Three of the mutations were nonsense, and two were frameshift; all are predicted to cause loss of function either through nonsense-mediated mRNA decay or protein truncation. Clinical findings included developmental delay (6/6), hypotonia (6/6), behavioural problems (5/6), eye abnormalities (5/6), constipation (5/6), feeding difficulties (4/6), seizures (2/6) and sleep problems (2/6). All patients exhibited common dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies were also noted. CONCLUSIONS: Our case series show that loss-of-function mutations in WAC cause a recognisable genetic syndrome characterised by a neurocognitive phenotype and facial dysmorphism. Our data highly suggest that WAC haploinsufficiency is responsible for most of the phenotypic features associated with deletions encompassing 10p11.23.

BACKGROUND: Posterior vault distraction osteogenesis (PVDO) is believed to improve frontal contour in infants with syndromic craniosynostosis and turribrachycephaly. This study provides an objective craniometric analysis to determine how PVDO affects anterior cranial morphology. METHODS: A retrospective chart review of patients who underwent PVDO was performed. Inclusion criteria included pre- and postoperative computed tomography (CT) scans within 3 months before surgery and another 1 to 6 months after device removal. Volumetric and craniometric data were derived using Mimics software and compared using paired t-test and Wilcoxon rank-sum test. RESULTS: About 65 patients underwent PVDO, and 13 patients met inclusion criteria. Mean age at intervention was 3.4 ± 4.2 years. Total cranial volume increased 249 ± 159 cm in all patients (P = 0.0001) and 380 ± 128 cm in patients younger than 1 year of age (n = 6, P =0 .0008). Supraorbital retrusion decreased from 5.44 ± 3.89 to 4.54 ± 3.91 mm postoperatively (P = 0.0004), decreasing significantly in patients without previous frontal surgery and not in those with previous frontal surgery (P = 0.2115; comparison P = 0.0047). Basofrontal angle decreased by 2.92 ± 2.16 degrees (P = 0.0004) with a greater decrease of 3.33±2.68 degrees in those younger than 12 months (P = 0.0289) and 2.58±1.74 degrees in those older (P = 0.0079). No change was found in anterior cranial height and anterofrontal angle (P > 0.05). CONCLUSION: PVDO improves frontal contour by decreasing supraorbital retrusion and reducing frontal bossing in syndromic craniosynostosis patients with turribrachycephaly. When combined with its demonstrated efficacy for cranial expansion, these frontal changes likely reinforce PVDO's ability to influence the timing of, and to a degree, the need for frontal surgery in this group.

Objectives: Multicenter data on the characteristics and outcomes of children hospitalized with coronavirus disease 2019 are limited. Our objective was to describe the characteristics, ICU admissions, and outcomes among children hospitalized with coronavirus disease 2019 using Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: Coronavirus Disease 2019 registry. Design: Retrospective study. Setting: Society of Critical Care Medicine Viral Infection and Respiratory Illness Universal Study (Coronavirus Disease 2019) registry. Patients: Children (&lt; 18 yr) hospitalized with coronavirus disease 2019 at participating hospitals from February 2020 to January 2021. Interventions: None. Measurements and Main Results: The primary outcome was ICU admission. Secondary outcomes included hospital and ICU duration of stay and ICU, hospital, and 28-day mortality. A total of 874 children with coronavirus disease 2019 were reported to Viral Infection and Respiratory Illness Universal Study registry from 51 participating centers, majority in the United States. Median age was 8 years (interquartile range, 1.25–14 yr) with a male:female ratio of 1:2. A majority were non-Hispanic (492/874; 62.9%). Median body mass index ( n = 817) was 19.4 kg/m 2 (16–25.8 kg/m 2 ), with 110 (13.4%) overweight and 300 (36.6%) obese. A majority (67%) presented with fever, and 43.2% had comorbidities. A total of 238 of 838 (28.2%) met the Centers for Disease Control and Prevention criteria for multisystem inflammatory syndrome in children, and 404 of 874 (46.2%) were admitted to the ICU. In multivariate logistic regression, age, fever, multisystem inflammatory syndrome in children, and pre-existing seizure disorder were independently associated with a greater odds of ICU admission. Hospital mortality was 16 of 874 (1.8%). Median (interquartile range) duration of ICU ( n = 379) and hospital ( n = 857) stay were 3.9 days (2–7.7 d) and 4 days (1.9–7.5 d), respectively. For patients with 28-day data, survival was 679 of 787, 86.3% with 13.4% lost to follow-up, and 0.3% deceased. Conclusions: In this observational, multicenter registry of children with coronavirus disease 2019, ICU admission was common. Older age, fever, multisystem inflammatory syndrome in children, and seizure disorder were independently associated with ICU admission, and mortality was lower among children than mortality reported in adults.

OBJECTIVES: To describe the Children's Hospital Association's Improving Pediatric Sepsis Outcomes sepsis definitions and the identified patients; evaluate the definition using a published framework for evaluating sepsis definitions. DESIGN: Observational cohort. SETTING: Multicenter quality improvement collaborative of 46 hospitals from January 2017 to December 2018, excluding neonatal ICUs. PATIENTS: Improving Pediatric Sepsis Outcomes Sepsis was defined by electronic health record evidence of suspected infection and sepsis treatment or organ dysfunction. A more severely ill subgroup, Improving Pediatric Sepsis Outcomes Critical Sepsis, was defined, approximating septic shock. INTERVENTIONS: Participating hospitals identified patients, extracted data, and transferred de-identified data to a central data warehouse. The definitions were evaluated across domains of reliability, content validity, construct validity, criterion validity, measurement burden, and timeliness. MEASUREMENTS AND MAIN RESULTS: Forty hospitals met data quality criteria across four electronic health record platforms. There were 23,976 cases of Improving Pediatric Sepsis Outcomes Sepsis, including 8,565 with Improving Pediatric Sepsis Outcomes Critical Sepsis. The median age was 5.9 years. There were 10,316 (43.0%) immunosuppressed or immunocompromised patients, 4,135 (20.3%) with central lines, and 2,352 (11.6%) chronically ventilated. Among Improving Pediatric Sepsis Outcomes Sepsis patients, 60.8% were admitted to intensive care, 26.4% had new positive-pressure ventilation, and 19.7% received vasopressors. Median hospital length of stay was 6.0 days (3.0-13.0 d). All-cause 30-day in-hospital mortality was 958 (4.0%) in Improving Pediatric Sepsis Outcomes Sepsis; 541 (6.3%) in Improving Pediatric Sepsis Outcomes Critical Sepsis. The Improving Pediatric Sepsis Outcomes Sepsis definitions demonstrated strengths in content validity, convergent construct validity, and criterion validity; weakness in reliability. Improving Pediatric Sepsis Outcomes Sepsis definitions had significant initial measurement burden (median time from case completion to submission: 15 mo [interquartile range, 13-18 mo]); timeliness improved once data capture was established (median, 26 d; interquartile range, 23-56 d). CONCLUSIONS: The Improving Pediatric Sepsis Outcomes Sepsis definitions demonstrated feasibility for large-scale data abstraction. The patients identified provide important information about children treated for sepsis. When operationalized, these definitions enabled multicenter identification and data aggregation, indicating practical utility for quality improvement.

OBJECTIVE To describe the impact of obesity on disease severity and outcomes of coronavirus disease 2019 (COVID-19) among hospitalized children. METHODS This retrospective cohort study from the Society of Critical Care Medicine Viral Respiratory Illness Universal Study registry included all children hospitalized with COVID-19 from March 2020 to January 2021. Obesity was defined by Centers for Disease Control and Prevention BMI or World Health Organization weight for length criteria. Critical illness definition was adapted from National Institutes of Health criteria of critical COVID. Multivariate mixed logistic and linear regression was performed to calculate the adjusted odds ratio of critical illness and the adjusted impact of obesity on hospital length of stay. RESULTS Data from 795 patients (96.4% United States) from 45 sites were analyzed, including 251 (31.5%) with obesity and 544 (68.5%) without. A higher proportion of patients with obesity were adolescents, of Hispanic ethnicity, and had other comorbidities. Those with obesity were also more likely to be diagnosed with multisystem inflammatory syndrome in children (35.7% vs 28.1%, P = .04) and had higher ICU admission rates (57% vs 44%, P &amp;lt; .01) with more critical illness (30.3% vs 18.3%, P &amp;lt; .01). Obesity had more impact on acute COVID-19 severity than on multisystem inflammatory syndrome in children presentation. The adjusted odds ratio for critical illness with obesity was 3.11 (95% confidence interval: 1.8–5.3). Patients with obesity had longer adjusted length of stay (exponentiated parameter estimate 1.3; 95% confidence interval: 1.1–1.5) compared with patients without obesity but did not have increased mortality risk due to COVID-19 (2.4% vs 1.5%, P = .38). CONCLUSION In a large, multicenter cohort, a high proportion of hospitalized children from COVID-19 had obesity as comorbidity. Furthermore, obesity had a significant independent association with critical illness.

Adolescent insomnia is a common condition that negatively impacts a developing young adult's mental and physical health. While the treatment of adult insomnia has been standardized, the treatment of pediatric insomnia is very practitioner-dependent and few large-scale studies are available to determine a standard recommended practice. There is great hope that as the adolescent medicine and sleep medicine fields flourish, larger cohort analyses will be performed to determine the prevalence and precipitating factors of adolescent insomnia, allowing for standardized treatment recommendations and systematic efforts to make these recommendations available to all adolescents.

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.