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In: JAMA, American Medical Association (AMA), Vol. 327, No. 2 ( 2022-01-11), p. 129-

Type of Medium: Online Resource

ISSN: 0098-7484

URL: Article

DOI: 10.1001/jama.2021.23182

Language: English

Publisher: American Medical Association (AMA)

Publication Date: 2022

detail.hit.zdb_id: 2958-0

detail.hit.zdb_id: 2018410-4

SSG: 5,21

In: Journal of Thrombosis and Haemostasis, Elsevier BV, Vol. 20, No. 1 ( 2022-01), p. 133-137

Type of Medium: Online Resource

ISSN: 1538-7836

URL: Article

DOI: 10.1111/jth.15548

Language: English

Publisher: Elsevier BV

Publication Date: 2022

detail.hit.zdb_id: 2099291-9

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 635-635

Abstract: Introduction Incidence of pediatric hospital-acquired venous thromboembolism (HA-VTE) is increasing raising concern for acute and chronic sequelae and impact on the health care system. This has prompted many pediatric centers to implement prophylaxis programs despite the lack of a validated risk-assessment model (RAM) or evidence of a favorable risk/benefit ratio for pharmacologic prophylaxis. The multi-center Children's Hospital-Acquired Thrombosis (CHAT) Consortium was created in 2014 to derive RAMs with subsequent prospective validation (i.e. CHAT 1901, the second study from the CHAT Consortium). We present the CHAT RAMs using traditional biostatistical (CHAT-TB) and machine learning (CHAT-ML) methods. Methods The first project of the CHAT Consortium was an eight-center, retrospective, case-control study of subjects aged 0-21 years diagnosed with a radiographic-confirmed, symptomatic HA-VTE and frequency-matched controls (by year and hospital) from January 1, 2012 through December 31, 2016. Controls were randomly sampled from the complete list of children without HA-VTE hospitalized and the sampling proportion of controls with hospital stay & lt; 48 hours was 20%. CHAT-TB: Weighted logistic regression examined univariate effects of variables known at baseline (prior to and on day of admission) on incidence of symptomatic HA-VTE. Key predictors with sufficient frequency and significance in univariate analyses progressed as candidates in the multivariable RAM developed via the Lasso method. Clinically important interaction effects were tested separately and considered a candidate predictor when the p-value of the interaction term was & lt; 0.10. Five approximately equal-sized samples were used for internal validation. The RAM was built independently in each sub-sample and the model fit was tested in the n - sub-sample cohort. Receiver operating characteristic (ROC) curves were used to assess performance in both a model re-substitution and average of the 5-sample internal validation subsets. CHAT-ML: We developed and evaluated four machine learning (ML) models (adaptive boosting, random forest, gradient boosting, and logistic regression), and the most accurate RAM was selected by comparing the relationship of model specificity and sensitivity in ROC curves. ML modelling consists of: pre-processing and feature extraction, data profiling and exploration, model selection, training, and testing, model re-calibration in partnership with subject-matter experts. With more than 250 variables for each patient, lasso regression was utilized to reduce the number of features to have only those with non-zero weight in the regression. We then divided the dataset into training (n=1250) and test (n=540) groups and report the F1 score, i.e. the harmonic mean of precision (i.e. positive predictive value) and recall (i.e. sensitivity) which is used to measure accuracy of a ML classifier. Results Demographics are summarized in Table 1. CHAT-TB: Significant predictors from the weighted logistic regression model are shown in Table 2 and ROC curves from the model re-substitution and 5-sample internal validation demonstrate precision with AUC of 79.9% (CI: 77.7-82.1%) and 77.9% (75.6-80.2%), respectively. CHAT-ML: Significant clinical variables included: change in mobility as assessed by BradenQ scoring, CVC, congenital heart disease, presence of a complex chronic condition (Feudtner 2014), contraindication to VTE prophylaxis (Table 3), ICU admission, infection, and change in platelet count. Figure 1 shows that gradient boosting outperformed other models via area under the ROC curve (AUC=0.95) and F1-score (0.89). Adaptive boosting also performed well with AUC=0.93 and F1-score (0.87). Discussion We present two novel RAMs from the CHAT Consortium. The CHAT RAM-TB and RAM-ML demonstrate sufficient performance for prospective validation and RAM-ML shows a stronger AUC. CHAT 1901 is designed to validate the RAMs, assess performance individually and comparatively, and develop risk-assessment calculators for clinical use and/or integration into the electronic health record (specific to the CHAT-ML, a visual analytics application will provide an interface for clinicians to enter information on significant predictors and receive a calculated risk score). Disclosures Mahajerin: Spark: Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees; Alexion: Speakers Bureau. Jaffray:CSL Behring: Research Funding. Croteau:Bayer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Octapharma: Honoraria. Silvey:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees. Goldenberg:NIH: Other: research support and salary support. Young:Kedrion: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Bioverativ/Sanofi: Consultancy, Honoraria; Grifols: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-126128

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1150-1150

Abstract: Introduction Incidence of hospital-acquired venous thromboembolism (HA-VTE) in children has been increasing in the absence of proven effective preventative interventions. To decrease the incidence of HA-VTE, we must first identify children at the highest risk by creating a risk assessment model (RAM). Critically ill children, especially those with a central venous catheter (CVC), inflammatory condition and/or prolonged hospital stay have been identified as high-risk. To date, studies of HA-VTE in critically ill children have only been at single-center and have not been well-validated in diverse populations. The Children's Hospital-Acquired Thrombosis (CHAT) consortium established a large multicenter Registry to develop and validate pediatric RAMs for HA-VTE. This multicenter study aimed to derive a RAM for HA-VTE among critically ill children (RAM-ICU) performed upon admission/transfer to a pediatric intensive care unit (PICU). The CHAT Registry consists of retrospectively-identified, imaging confirmed cases of symptomatic HA-VTE and hospitalized controls (without HA-VTE) aged 0-21 years from eight U.S. centers. Controls were frequency-matched by year of admission and center. Details on demographics, medical history and hospital course were extracted from the medical record. For the RAM-ICU, only HA-VTE subjects and controls admitted/transferred into an ICU were included. Subjects who had a cardiac surgery up to 2 weeks prior to ICU admission were excluded. Fourteen variables that were present at or within 24 hours of ICU admission/transfer were evaluated by univariate logistic regression. These included demographics, medications, medical history, recent surgeries, mechanical ventilation, patient mobility and presence of a CVC. Those variables with p-values of 〈 0.1 in univariate analyses were included in a multivariable logistic regression model. For the final model, variables with p-values of 〈 0.05 were considered statistically significant. Results Out of 1172 HA-VTE cases and 952 controls in the Registry, 535 cases and 188 controls met inclusion criteria for the RAM-ICU. With discrepant subject distribution as expected due to previously reported increased incidence of HA-VTE in critically ill children. Median age was 0.8 years (IQR 0.1-10.2) for cases and 2.6 years (IQR 0.2-8.35) for controls. Fifty-eight percent of cases and 50% of controls were male. The Table presents the unadjusted analysis which revealed eight variables associated with HA-VTE (P 〈 0.05): recent hospitalization (prior to current hospitalization), procedure with intravascular instruments within 24 hours of ICU admission, CVC present or placed within 24 hours of ICU admission, congenital heart disease, autoimmune disease or serious infection (includes autoimmune/inflammatory disorder, inflammatory bowel disease, juvenile rheumatoid arthritis, lupus, or major blood, organ or urinary infection), mechanical ventilation within 24 hours of ICU admission, and other past medical history (Table). Variables that remained statistically-significant, independent risk factors in an adjusted (multivariable) logistic regression included presence of a CVC (4.53; 95% CI=2.80-7.33), congenital heart disease (OR=2.32; 95% CI=1.42-3.78), and autoimmune disease or serious infection (OR=2.52; 95% CI=1.52-4.17) (Table). Conclusions With the increasing incidence of pediatric HA-VTE, there is an urgent need to identify children at high risk and incorporate risk reduction methods. The CHAT RAM-ICU represents the largest, multicenter pediatric study evaluating HA-VTE risk in children admitted/transferred to an ICU, with 535 HA-VTE cases and 188 controls. Recent placement of a CVC, congenital heart disease, and autoimmune disease or serious infection are significant, independent risk factors for HA-VTE in critically ill children. We will prospectively validate the RAM-ICU in a multicenter prospective study funded via the Hemophilia and Thrombosis Research Society. Disclosures Jaffray: CSL Behring: Research Funding. Mahajerin:Alexion: Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark: Speakers Bureau. Silvey:Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees. Croteau:Spark Therapeutics: Research Funding; Spark Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Shire: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; Pfizer: Research Funding; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Octapharma: Honoraria. Young:CSL Behring: Consultancy, Honoraria; Bioverativ/Sanofi: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria. Goldenberg:NIH: Other: research support and salary support.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-130788

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Research and Practice in Thrombosis and Haemostasis, Elsevier BV, Vol. 6, No. 7 ( 2022-10), p. e12810-

Type of Medium: Online Resource

ISSN: 2475-0379

URL: Article

DOI: 10.1002/rth2.12810

Language: English

Publisher: Elsevier BV

Publication Date: 2022

detail.hit.zdb_id: 2901840-7

In: Pediatric Critical Care Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 23, No. 1 ( 2022-01), p. e1-e9

Abstract: To create a risk model for hospital-acquired venous thromboembolism in critically ill children upon admission to an ICU. DESIGN: Case-control study. SETTING: ICUs from eight children’s hospitals throughout the United States. SUBJECTS: Critically ill children with hospital-acquired venous thromboembolism (cases) 0–21 years old and similar children without hospital-acquired venous thromboembolism (controls) from January 2012 to December 2016. Children with a recent cardiac surgery, asymptomatic venous thromboembolism, or a venous thromboembolism diagnosed before ICU admission were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The multi-institutional Children’s Hospital-Acquired Thrombosis registry was used to identify cases and controls. Multivariable logistic regression was used to determine the association between hospital-acquired venous thromboembolism and putative risk factors present at or within 24 hours of ICU admission to develop the final model. A total of 548 hospital-acquired venous thromboembolism cases (median age, 0.8 yr; interquartile range, 0.1–10.2) and 187 controls (median age, 2.4 yr; interquartile range, 0.2–8.3) were analyzed. In the multivariable model, recent central venous catheter placement (odds ratio, 4.4; 95% CI, 2.7–7.1), immobility (odds ratio 3.6, 95% CI, 2.1–6.2), congenital heart disease (odds ratio 2.9, 95% CI, 1.7-4.7), length of hospital stay prior to ICU admission greater than or equal to 3 days (odds ratio, 2.5; 95% CI, 1.1–5.6), and history of autoimmune/inflammatory condition or current infection (odds ratio, 2.1; 95% CI, 1.2–3.4) were each independently associated with hospital-acquired venous thromboembolism. The risk model had an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.73–0.84). CONCLUSIONS: Using the multicenter Children’s Hospital-Acquired Thrombosis registry, we identified five independent risk factors for hospital-acquired venous thromboembolism in critically ill children, deriving a new hospital-acquired venous thromboembolism risk assessment model. A prospective validation study is underway to define a high-risk group for risk-stratified interventional trials investigating the efficacy and safety of prophylactic anticoagulation in critically ill children.

Type of Medium: Online Resource

ISSN: 1529-7535

URL: Article

DOI: 10.1097/PCC.0000000000002826

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2022

detail.hit.zdb_id: 2070997-3

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 5-6

Abstract: Introduction: Appropriate timing of central venous Catheter (CVC) removal in children after the diagnosis of a CVC-related thrombosis (CRT) is poorly characterized. Due to the risk of embolization, ASH guidelines recommend initiating anticoagulation before CVC removal, but without a specified treatment period before CVC removal. An abstract from the 2019 ASH meeting did not find an increase in embolization rates when comparing anticoagulation treatment & lt; or & gt;48 hours prior to removal (Houghton et al, Blood 2019) in adult cancer patients with upper extremity CRT. This current study aimed to use data within the multi-institutional Children's Hospital-Acquired Thrombosis (CHAT) Consortium Registry to evaluate the incidence of symptomatic pulmonary embolism (PE) after CVC removal. Methods: The CHAT Registry is a retrospective cohort study which consists of detailed data from children aged 0-21 years with a hospital-acquired venous thromboembolism (HA-VTE) from eight U.S. centers. Eligible participants were those with a CRT. Participants were excluded if the diagnosis of thrombosis was & gt;/= 3 days after CVC removal or if the CRT was due to a failed attempt at inserting a CVC. CHAT included details on demographics, medical history, CVC insertion and removal dates, anticoagulation start and stop dates and secondary outcomes, such as PE were extracted for analysis. Participants were divided into three groups, those in which (1) CVC removal occurred without anticoagulation initiation, (2) CVC removal occurred & lt;48 hours after starting anticoagulation, and (3) CVC removal occurred ≥48 hours after starting anticoagulation (Figure 1). Results: A total of 687 CRT events from 663 participants were included. The median age at hospital admission was 1.4 years (IQR 0.1, 11.3) The majority of participants were male, 57% (378), 54% were non-Hispanic (359) and 46% were White (307). The most common past medical history for all participants with a CRT was congenital heart disease (22%, n=148) followed by cancer (11%, n=71), metabolic or mitochondrial disorder (3%, n=22) and inflammatory bowel disease (3%, n=21). For 76 CRT events the CVC was not removed during the participant's hospitalization or the removal date was unknown, therefore these events were excluded from further analysis. Anticoagulation was not initiated for 72 CRT events and for these events the median time from VTE diagnosis to CVC removal was one day (range 0-5.5). For the events that received anticoagulation there were 311 with CVC removal & lt;48 hours and 228 events with CVC removal ≥48 hours (Table 1). Most of the CRT events with CVC removal & lt;48 hours were in the lower extremity (52%, n=161) compared to CRT events with CVC removal ≥48 hours, which were mostly in the upper extremity (56%, n=127). A peripherally inserted central catheter was the most common CVC type regardless of group, followed by a temporary femoral line (Table 1). For all 611 CRT events in which the CVC was removed, there was only one case of PE (0.16%), which occurred & lt;48 hours after CVC removal and initiation of anticoagulation (Figure 1). Conclusions: While current guidelines suggest anticoagulation before removal of CVCs in the setting of CRT to prevent embolization and PE, removal appears safe regardless of duration of anticoagulation before CVC removal in this pediatric cohort. These findings support need to substantiate the findings our CHAT consortium's ongoing prospective cohort study, but while waiting for these results, potential PEs should not weigh heavily in providers clinical decision making on timing of CVC removal. Disclosures Jaffray: CSL Behring: Research Funding; Octapharma: Other: Unrestricted funds for physician education. Baumann Kreuziger:CSL Behring: Consultancy; Quercegen pharmaceuticals: Consultancy. Mahajerin:Spark Therapeutics, Alexion, Genentech, Inc.: Speakers Bureau. Croteau:Hemophilia Federation of America: Honoraria; National Hemophilia Foundation: Honoraria; Sigilon Therapeutics: Consultancy; ATHN: Research Funding; Spark Therapeutics: Research Funding; CSL-Behring: Consultancy; Novo Nordisk: Research Funding; Pfizer: Consultancy; Genentech: Consultancy; Bayer: Consultancy. Young:BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria; Bayer, CSL Behring, Freeline, UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Goldenberg:Academic Research Organization CPC Clinical Research: Consultancy; Daiici Sankyo: Consultancy; Novartis: Consultancy; Chiesi: Consultancy; Roshan Pharmaceuticals: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-137216

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Brain, Oxford University Press (OUP), Vol. 146, No. 4 ( 2023-04-19), p. 1420-1435

Abstract: Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes. Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA. Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive. Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia. The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila. Our results showed that two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals. The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila. These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function.

Type of Medium: Online Resource

ISSN: 0006-8950 , 1460-2156

URL: Article

DOI: 10.1093/brain/awac460

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2023

detail.hit.zdb_id: 1474117-9

SSG: 12

In: The Journal of Pediatrics, Elsevier BV, Vol. 228 ( 2021-01), p. 252-259.e1

Type of Medium: Online Resource

ISSN: 0022-3476

URL: Article

DOI: 10.1016/j.jpeds.2020.09.016

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 2005245-5

In: The American Journal of Human Genetics, Elsevier BV, Vol. 109, No. 9 ( 2022-09), p. 1563-1571

Type of Medium: Online Resource

ISSN: 0002-9297

URL: Article

DOI: 10.1016/j.ajhg.2022.08.005

Language: English

Publisher: Elsevier BV

Publication Date: 2022

detail.hit.zdb_id: 1473813-2

SSG: 12