Cohen Children's Medical Center

IMPORTANCE: Septic shock currently refers to a state of acute circulatory failure associated with infection. Emerging biological insights and reported variation in epidemiology challenge the validity of this definition. OBJECTIVE: To develop a new definition and clinical criteria for identifying septic shock in adults. DESIGN, SETTING, AND PARTICIPANTS: The Society of Critical Care Medicine and the European Society of Intensive Care Medicine convened a task force (19 participants) to revise current sepsis/septic shock definitions. Three sets of studies were conducted: (1) a systematic review and meta-analysis of observational studies in adults published between January 1, 1992, and December 25, 2015, to determine clinical criteria currently reported to identify septic shock and inform the Delphi process; (2) a Delphi study among the task force comprising 3 surveys and discussions of results from the systematic review, surveys, and cohort studies to achieve consensus on a new septic shock definition and clinical criteria; and (3) cohort studies to test variables identified by the Delphi process using Surviving Sepsis Campaign (SSC) (2005-2010; n = 28,150), University of Pittsburgh Medical Center (UPMC) (2010-2012; n = 1,309,025), and Kaiser Permanente Northern California (KPNC) (2009-2013; n = 1,847,165) electronic health record (EHR) data sets. MAIN OUTCOMES AND MEASURES: Evidence for and agreement on septic shock definitions and criteria. RESULTS: The systematic review identified 44 studies reporting septic shock outcomes (total of 166,479 patients) from a total of 92 sepsis epidemiology studies reporting different cutoffs and combinations for blood pressure (BP), fluid resuscitation, vasopressors, serum lactate level, and base deficit to identify septic shock. The septic shock-associated crude mortality was 46.5% (95% CI, 42.7%-50.3%), with significant between-study statistical heterogeneity (I2 = 99.5%; τ2 = 182.5; P < .001). The Delphi process identified hypotension, serum lactate level, and vasopressor therapy as variables to test using cohort studies. Based on these 3 variables alone or in combination, 6 patient groups were generated. Examination of the SSC database demonstrated that the patient group requiring vasopressors to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L (18 mg/dL) after fluid resuscitation had a significantly higher mortality (42.3% [95% CI, 41.2%-43.3%]) in risk-adjusted comparisons with the other 5 groups derived using either serum lactate level greater than 2 mmol/L alone or combinations of hypotension, vasopressors, and serum lactate level 2 mmol/L or lower. These findings were validated in the UPMC and KPNC data sets. CONCLUSIONS AND RELEVANCE: Based on a consensus process using results from a systematic review, surveys, and cohort studies, septic shock is defined as a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone. Adult patients with septic shock can be identified using the clinical criteria of hypotension requiring vasopressor therapy to maintain mean BP 65 mm Hg or greater and having a serum lactate level greater than 2 mmol/L after adequate fluid resuscitation.

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

OBJECTIVE: We developed clinical practice guidelines for congenital adrenal hyperplasia (CAH). PARTICIPANTS: The Task Force included a chair, selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), ten additional clinicians experienced in treating CAH, a methodologist, and a medical writer. Additional experts were also consulted. The authors received no corporate funding or remuneration. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. CONCLUSIONS: We recommend universal newborn screening for severe steroid 21-hydroxylase deficiency followed by confirmatory tests. We recommend that prenatal treatment of CAH continue to be regarded as experimental. The diagnosis rests on clinical and hormonal data; genotyping is reserved for equivocal cases and genetic counseling. Glucocorticoid dosage should be minimized to avoid iatrogenic Cushing's syndrome. Mineralocorticoids and, in infants, supplemental sodium are recommended in classic CAH patients. We recommend against the routine use of experimental therapies to promote growth and delay puberty; we suggest patients avoid adrenalectomy. Surgical guidelines emphasize early single-stage genital repair for severely virilized girls, performed by experienced surgeons. Clinicians should consider patients' quality of life, consulting mental health professionals as appropriate. At the transition to adulthood, we recommend monitoring for potential complications of CAH. Finally, we recommend judicious use of medication during pregnancy and in symptomatic patients with nonclassic CAH.

BACKGROUND: Crohn's disease and ulcerative colitis are complex disorders with some shared and many unique predisposing genes. Accurate phenotype classification is essential in determining the utility of genotype-phenotype correlation. The Montreal Classification of IBD has several weaknesses with respect to classification of children. The dynamic features of pediatric disease phenotype (change in disease location and behavior over time, growth failure) are not sufficiently captured by the current Montreal Classification. METHODS: Focusing on facilitating research in pediatric inflammatory bowel disease (IBD), and creating uniform standards for defining IBD phenotypes, an international group of pediatric IBD experts met in Paris, France to develop evidence-based consensus recommendations for a pediatric modification of the Montreal criteria. RESULTS: Important modifications developed include classifying age at diagnosis as A1a (0 to <10 years), A1b (10 to <17 years), A2 (17 to 40 years), and A3 (>40 years), distinguishing disease above the distal ileum as L4a (proximal to ligament of Treitz) and L4b (ligament of Treitz to above distal ileum), allowing both stenosing and penetrating disease to be classified in the same patient (B2B3), denoting the presence of growth failure in the patient at any time as G(1) versus G(0) (never growth failure), adding E4 to denote extent of ulcerative colitis that is proximal to the hepatic flexure, and denoting ever severe ulcerative colitis during disease course by S1. CONCLUSIONS: These modifications are termed the Paris Classification. By adhering to the Montreal framework, we have not jeopardized or altered the ability to use this classification for adult onset disease or by adult gastroenterologists.

Newborn screening Cost-effectiveness 1.1 We recommend that all newborn screening programs incorporate screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. (1|s) 1.2 We recommend that first-tier screens use 17hydroxyprogesterone assays standardized to a common technology with norms stratified by gestational age. (1|s) Technical remark: Clinicians should be aware that immunoassays are still in use and remain a source of false-positive results. Specificity may be improved with organic extraction to remove cross-reacting substances. 1.3 We recommend that screening laboratories employ a second-tier screen by liquid chromatographytandem mass spectrometry in preference to all other

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

These clinical practice guidelines are an update of the guidelines published by the Infectious Diseases Society of America (IDSA) in 2009, prior to the 2009 H1N1 influenza pandemic. This document addresses new information regarding diagnostic testing, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal influenza. It is intended for use by primary care clinicians, obstetricians, emergency medicine providers, hospitalists, laboratorians, and infectious disease specialists, as well as other clinicians managing patients with suspected or laboratory-confirmed influenza. The guidelines consider the care of children and adults, including special populations such as pregnant and postpartum women and immunocompromised patients.

Interactions between the host and gut microbial community likely contribute to Crohn disease (CD) pathogenesis; however, direct evidence for these interactions at the onset of disease is lacking. Here, we characterized the global pattern of ileal gene expression and the ileal microbial community in 359 treatment-naive pediatric patients with CD, patients with ulcerative colitis (UC), and control individuals. We identified core gene expression profiles and microbial communities in the affected CD ilea that are preserved in the unaffected ilea of patients with colon-only CD but not present in those with UC or control individuals; therefore, this signature is specific to CD and independent of clinical inflammation. An abnormal increase of antimicrobial dual oxidase (DUOX2) expression was detected in association with an expansion of Proteobacteria in both UC and CD, while expression of lipoprotein APOA1 gene was downregulated and associated with CD-specific alterations in Firmicutes. The increased DUOX2 and decreased APOA1 gene expression signature favored oxidative stress and Th1 polarization and was maximally altered in patients with more severe mucosal injury. A regression model that included APOA1 gene expression and microbial abundance more accurately predicted month 6 steroid-free remission than a model using clinical factors alone. These CD-specific host and microbe profiles identify the ileum as the primary inductive site for all forms of CD and may direct prognostic and therapeutic approaches.

tumor suppressor gene encoding p53, a transcription factor triggered as a protective cellular mechanism against different stressors. Loss of p53 function renders affected individuals highly susceptible to a broad range of solid and hematologic cancers. It has recently become evident that children and adults with LFS benefit from intensive surveillance aimed at early tumor detection. In October 2016, the American Association for Cancer Research held a meeting of international LFS experts to evaluate the current knowledge on LFS and propose consensus surveillance recommendations. Herein, we briefly summarize clinical and genetic aspects of this aggressive cancer predisposition syndrome. In addition, the expert panel concludes that there are sufficient existing data to recommend that all patients with LFS be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established. Specifically, the panel recommends adoption of a modified version of the "Toronto protocol" that includes a combination of physical exams, blood tests, and imaging. The panel also recommends that further research be promoted to explore the feasibility and effectiveness of these risk-adapted surveillance and cancer prevention strategies while addressing the psychosocial needs of individuals and families with LFS.

OBJECTIVE: To determine the safety and efficacy of BAY x 1351, a murine monoclonal antibody to recombinant human tumor necrosis factor (TNF)-alpha, in patients with sepsis. DESIGN: An international, multicenter, prospective, placebo-controlled trial in patients with sepsis, stratified into shock/nonshock groups. SETTING: Forty acute clinical care facilities in 14 countries. PATIENTS: Of the 564 patients enrolled in the study, 553 patients received study drug or placebo. INTERVENTIONS: Patients received 15 mg/kg or 3 mg/kg of BAY x 1351, or placebo, as a single intravenous infusion. MEASUREMENTS AND MAIN RESULTS: The patients were well matched for severity of illness and for risk factors known to influence the outcome of sepsis. There was no difference in 28-day mortality rates between groups (placebo group 66 [39.5%] of 167;3 mg/kg group 57 [31.5%] of 181; 15 mg/kg group 87 [42.4%] of 205). Approximately 9 months after this study had begun, an interim safety examination of NORASEPT, a North American Sepsis Trial using the same monoclonal antibody, indicated that there was no benefit to patients in the nonshock group and further enrollment of these nonshock septic patients into INTERSEPT was stopped. The analysis therefore focused on the 420 patients in shock. The primary efficacy variable was the 28-day, all-cause mortality rate: placebo group 57 (42.9%) of 133; 3-mg/kg group 51 (36.7%) of 139; and 15-mg/kg group 66 (44.6%) of 148 (not significant). Two secondary efficacy variables were identified prospectively: shock reversal and frequency of organ failures. Life-table analysis showed that in patients who survived 28 days, there was a more rapid reversal of shock in both treatment groups compared with placebo (15-mg/kg group vs. placebo group log-rank statistic p = .007, 3-mg/kg group vs. placebo group p = .01). Similarly, in patients surviving 28 days, there was a significant delay in the time to the onset of first organ failure (log rank 15 mg/kg vs. placebo p = .03, 3 mg/kg vs. placebo p = .07), and more patients in the placebo group developed at least one organ failure: 15-mg/kg group 33 (40.2%) of 82; 3-mg/kg group 39 (44.3%) of 88; and placebo group 45 (59.2%) of 76 (15 mg/kg vs. placebo p = .03, 3 mg/kg vs. placebo p = .06). No significant adverse events were associated with the monoclonal antibody treatment. CONCLUSIONS: INTERSEPT provides additional clinical data implicating TNF-alpha as an integral mediator of septic shock. The study suggested a possible role for anti-TNF antibody as adjunctive therapy, but this possibility requires confirmation by another clinical trial.

Abstract Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments.

PURPOSE: To evaluate the DSM-5 diagnosis of Avoidant/Restrictive Food Intake Disorder (ARFID) in children and adolescents with poor eating not associated with body image concerns. METHODS: A retrospective case-control study of 8-18-year-olds, using a diagnostic algorithm, compared all cases with ARFID presenting to seven adolescent-medicine eating disorder programs in 2010 to a randomly selected sample with anorexia nervosa (AN) and bulimia nervosa (BN). Demographic and clinical information were recorded. RESULTS: Of 712 individuals studied, 98 (13.8%) met ARFID criteria. Patients with ARFID were younger than those with AN (n = 98) or BN (n = 66), (12.9 vs. 15.6 vs. 16.5 years), had longer durations of illness (33.3 vs. 14.5 vs. 23.5 months), were more likely to be male (29% vs. 15% vs. 6%), and had a percent median body weight intermediate between those with AN or BN (86.5 vs. 81.0 and 107.5). Patients with ARFID included those with selective (picky) eating since early childhood (28.7%); generalized anxiety (21.4%); gastrointestinal symptoms (19.4%); a history of vomiting/choking (13.2%); and food allergies (4.1%). Patients with ARFID were more likely to have a comorbid medical condition (55% vs. 10% vs. 11%) or anxiety disorder (58% vs. 35% vs. 33%) and were less likely to have a mood disorder (19% vs. 31% vs. 58%). CONCLUSIONS: Patients with ARFID were demographically and clinically distinct from those with AN or BN. They were significantly underweight with a longer duration of illness and had a greater likelihood of comorbid medical and/or psychiatric symptoms.

Oxygen saturation in the arterial blood (SaO2) provides information on the adequacy of respiratory function. SaO2 can be assessed noninvasively by pulse oximetry, which is based on photoplethysmographic pulses in two wavelengths, generally in the red and infrared regions. The calibration of the measured photoplethysmographic signals is performed empirically for each type of commercial pulse-oximeter sensor, utilizing in vitro measurement of SaO2 in extracted arterial blood by means of co-oximetry. Due to the discrepancy between the measurement of SaO2 by pulse oximetry and the invasive technique, the former is denoted as SpO2. Manufacturers of pulse oximeters generally claim an accuracy of 2%, evaluated by the standard deviation (SD) of the differences between SpO2 and SaO2, measured simultaneously in healthy subjects. However, an SD of 2% reflects an expected error of 4% (two SDs) or more in 5% of the examinations, which is in accordance with an error of 3%-4%, reported in clinical studies. This level of accuracy is sufficient for the detection of a significant decline in respiratory function in patients, and pulse oximetry has been accepted as a reliable technique for that purpose. The accuracy of SpO2 measurement is insufficient in several situations, such as critically ill patients receiving supplemental oxygen, and can be hazardous if it leads to elevated values of oxygen partial pressure in blood. In particular, preterm newborns are vulnerable to retinopathy of prematurity induced by high oxygen concentration in the blood. The low accuracy of SpO2 measurement in critically ill patients and newborns can be attributed to the empirical calibration process, which is performed on healthy volunteers. Other limitations of pulse oximetry include the presence of dyshemoglobins, which has been addressed by multiwavelength pulse oximetry, as well as low perfusion and motion artifacts that are partially rectified by sophisticated algorithms and also by reflection pulse oximetry.

OBJECT: Chronic subdural hematomas (SDHs) are more common among veterans and elderly persons than among members of the general population; however, precise incidence rates are unknown. The purposes of this study were 1) to determine the current incidence of chronic SDH in a US Veterans Administration (VA) population and 2) to create a mathematical model for determining the current and future incidence of chronic SDH as a function of population age, sex, and comorbidity in the United States VA and civilian populations. METHODS: To determine the actual number of veterans who received a radiographic diagnosis and surgical treatment for SDH during 2000-2012, the authors used the VISN03 VA database. On the basis of this result and data from outside the United States, they then created a mathematical model accounting for age, sex, and alcohol consumption to predict the incidence of SDH in the VA and civilian populations during 2012-2040. RESULTS: Of 875,842 unique (different patient) visits to a VA hospital during the study period, 695 new SDHs were identified on CT images. Of these 695 SDHs, 203 (29%) required surgical drainage. The incidence rate was 79.4 SDHs per 100,000 persons, and the age-standardized rate was 39.1±4.74 SDHs per 100,000 persons. The authors' model predicts that incidence rates of chronic SDH in aging United States VA and civilian populations will reach 121.4 and 17.4 cases per 100,000 persons, respectively, by 2030, at which time, approximately 60,000 cases of chronic SDH will occur each year in the United States. CONCLUSIONS: The incidence of chronic SDH is rising; SDH is projected to become the most common cranial neurosurgical condition among adults by the year 2030.

Abstract Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α 4 β 7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

Definitions for sepsis, septic shock, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) were developed by consensus conferences with the goal of achieving standardization of terminology and improved homogeneity of patient populations in clinical studies. Although such definitions have been useful in epidemiologic investigations, the criteria specified by the consensus conferences are broad and insufficiently specific to address the problem of heterogeneous mechanisms leading to clinical syndromes. An important challenge is to progress from clinical syndromes, as presently defined, to more specific entities that are delineated by alterations in specific immunologic or biochemical pathways. Such mechanistic definitions will provide more homogeneous groups of patients who can be identified at early stages of their clinical course. This approach encourages focused investigation of pathways leading to organ system dysfunction and death and, also, provides an efficient framework for the development of new therapies useful in critically ill patients.

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.

OBJECTIVE: In 2008, all 18 regional referral NICUs in New York state adopted central-line insertion and maintenance bundles and agreed to use checklists to monitor maintenance-bundle adherence and report checklist use. We sought to confirm whether adopting standardized bundles and using central-line maintenance checklists reduced central-line-associated bloodstream infections (CLABSI). METHODS: This was a prospective cohort study that enrolled all neonates with a central line who were hospitalized in any of 18 NICUs. Each NICU reported CLABSI and central-line utilization data and checklist use. We used χ(2) to compare CLABSI rates in the preintervention (January to December 2007) versus the postintervention (March to December 2009) periods and Poisson regression to model adjusted CLABSI rates. RESULTS: Each study period included more than 55 000 central-line days and more than 200 000 patient-days. CLABSI rates decreased 67% statewide (risk ratio: 0.33 [95% confidence interval: 0.27-0.41]; P < .0005); after adjusting for the altered central-line-associated bloodstream infection definition in 2008, by 40% (risk ratio: 0.60 [95% confidence interval: 0.48-0.75]; P < .0005). A total of 13 of 18 NICUs reported using maintenance checklists for 10% to 100% of central-line days. The checklist-use rate was associated with the CLABSI rate (coefficient: -0.57, P = .04). A total of 10 of 18 NICUs were independent CLABSI rate predictors, ranging from 1 site with greatly reduced risk (incidence rate ratio: 0.04, P < .0005) to 1 site with greatly increased risk (incidence rate ratio: 2.87, P < .0005). CONCLUSIONS: Although standardizing central-line care elements led to a significant statewide decline in NICU CLABSIs, site of care remains an independent risk factor. Using maintenance checklists reduced CLABSIs.