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Age-dependent association of obesity with COVID-19 severity in paediatric patients

Guzman, Benedict Vincent; Elbel, Brian; Jay, Melanie; Messito, Mary Jo; Curado, Silvia
BACKGROUND:Limited research has addressed the obesity-COVID-19 severity association in paediatric patients. OBJECTIVE:To determine whether obesity is an independent risk factor for COVID-19 severity in paediatric patients and whether age modifies this association. METHODS:SARS-CoV-2-positive patients at NYU Langone Health from 1 March 2020 to 3 January 2021 aged 0-21 years with available anthropometric measurements: weight, length/height and/or body mass index (BMI). Modified log-Poisson models were utilized for the analysis. Main outcomes were 1) hospitalization and 2) critical illness (intensive care unit [ICU] admission). RESULTS:One hundred and fifteen of four hundred and ninety-four (23.3%) patients had obesity. Obesity was an independent risk factor for critical illness (adjusted risk ratio [ARR] 2.02, 95% CI 1.17 to 3.48). This association was modified by age, with obesity related to a greater risk for critical illness in adolescents (13-21 years) [ARR 3.09, 95% CI 1.48 to 6.47], but not in children (0-12 years). Obesity was not an independent risk factor for hospitalization for any age. CONCLUSION/CONCLUSIONS:Obesity was an independent risk factor for critical illness in paediatric patients, and this association was modified by age, with obesity related to a greater risk for critical illness in adolescents, but not in children. These findings are crucial for patient risk stratification and care.
PMID: 34581027
ISSN: 2047-6310
CID: 5067422

Predicting childhood obesity using electronic health records and publicly available data

Hammond, Robert; Athanasiadou, Rodoniki; Curado, Silvia; Aphinyanaphongs, Yindalon; Abrams, Courtney; Messito, Mary Jo; Gross, Rachel; Katzow, Michelle; Jay, Melanie; Razavian, Narges; Elbel, Brian
BACKGROUND:Because of the strong link between childhood obesity and adulthood obesity comorbidities, and the difficulty in decreasing body mass index (BMI) later in life, effective strategies are needed to address this condition in early childhood. The ability to predict obesity before age five could be a useful tool, allowing prevention strategies to focus on high risk children. The few existing prediction models for obesity in childhood have primarily employed data from longitudinal cohort studies, relying on difficult to collect data that are not readily available to all practitioners. Instead, we utilized real-world unaugmented electronic health record (EHR) data from the first two years of life to predict obesity status at age five, an approach not yet taken in pediatric obesity research. METHODS AND FINDINGS/RESULTS:We trained a variety of machine learning algorithms to perform both binary classification and regression. Following previous studies demonstrating different obesity determinants for boys and girls, we similarly developed separate models for both groups. In each of the separate models for boys and girls we found that weight for length z-score, BMI between 19 and 24 months, and the last BMI measure recorded before age two were the most important features for prediction. The best performing models were able to predict obesity with an Area Under the Receiver Operator Characteristic Curve (AUC) of 81.7% for girls and 76.1% for boys. CONCLUSIONS:We were able to predict obesity at age five using EHR data with an AUC comparable to cohort-based studies, reducing the need for investment in additional data collection. Our results suggest that machine learning approaches for predicting future childhood obesity using EHR data could improve the ability of clinicians and researchers to drive future policy, intervention design, and the decision-making process in a clinical setting.
PMID: 31009509
ISSN: 1932-6203
CID: 3821342

Correction: Predicting childhood obesity using electronic health records and publicly available data

Hammond, Robert; Athanasiadou, Rodoniki; Curado, Silvia; Aphinyanaphongs, Yindalon; Abrams, Courtney; Messito, Mary Jo; Gross, Rachel; Katzow, Michelle; Jay, Melanie; Razavian, Narges; Elbel, Brian
[This corrects the article DOI: 10.1371/journal.pone.0215571.].
PMID: 31589654
ISSN: 1932-6203
CID: 4129312

T cell antigen receptor activation and actin cytoskeleton remodeling

Kumari, Sudha; Curado, Silvia; Mayya, Viveka; Dustin, Michael L
T cells constitute a crucial arm of the adaptive immune system and their optimal function is required for a healthy immune response. After the initial step of T cell-receptor (TCR) triggering by antigenic peptide complexes on antigen presenting cell (APC), the T cell exhibits extensive cytoskeletal remodeling. This cytoskeletal remodeling leads to the formation of an "immunological synapse" [1] characterized by regulated clustering, segregation and movement of receptors at the interface. Synapse formation regulates T cell activation and response to antigenic peptides and proceeds via feedback between actin cytoskeleton and TCR signaling. Actin polymerization participates in various events during the synapse formation, maturation, and eventually its disassembly. There is increasing knowledge about the actin effectors that couple TCR activation to actin rearrangements [2,3], and how defects in these effectors translate into impairment of T cell activation. In this review we aim to summarize and integrate parts of what is currently known about this feedback process. In addition, in light of recent advancements in our understanding of TCR triggering and translocation at the synapse, we speculate on the organizational and functional diversity of microfilament architecture in the T cell. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters.
PMID: 23680625
ISSN: 0006-3002
CID: 558302

"Cell biology meets physiology: functional organization of vertebrate plasma membranes"-the immunological synapse

Curado, Silvia; Kumari, Sudha; Dustin, Michael L
The immunological synapse (IS) is an excellent example of cell-cell communication, where signals are exchanged between two cells, resulting in a well-structured line of defense during adaptive immune response. This process has been the focus of several studies that aimed at understanding its formation and subsequent events and has led to the realization that it relies on a well-orchestrated molecular program that only occurs when specific requirements are met. The development of more precise and controllable T cell activation systems has led to new insights including the role of mechanotransduction in the process of formation of the IS and T cell activation. Continuous advances in our understanding of the IS formation, particularly in the context of T cell activation and differentiation, as well the development of new T cell activation systems are being applied to the establishment and improvement of immune therapeutical approaches.
PMID: 24210434
ISSN: 1063-5823
CID: 626942

T Cell Activation is Determined by the Number of Presented Antigens

Deeg, Janosch; Axmann, Markus; Matic, Jovana; Liapis, Anastasia; Depoil, David; Afrose, Jehan; Curado, Silvia; Dustin, Michael L; Spatz, Joachim P
Antigen recognition is a key event during T cell activation. Here, we introduce nanopatterned antigen arrays that mimic the antigen presenting cell surface during T cell activation. The assessment of activation related events revealed the requirement of a minimal density of 90-140 stimulating major histocompatibility complex class II proteins (pMHC) molecules per mum(2). We demonstrate that these substrates induce T cell responses in a pMHC dose-dependent manner and that the number of presented pMHCs dominates over local pMHC density.
PMID: 24117051
ISSN: 1530-6984
CID: 687462

T Lymphocyte Myosin IIA is Required for Maturation of the Immunological Synapse

Kumari, Sudha; Vardhana, Santosha; Cammer, Michael; Curado, Silvia; Santos, Luis; Sheetz, Michael P; Dustin, Michael L
The role of non-muscle myosin IIA (heavy chain encoded by the non-muscle myosin heavy chain 9 gene, Myh9) in immunological synapse formation is controversial. We have addressed the role of myosin IIA heavy chain protein (MYH9) in mouse T cells responding to MHC-peptide complexes and ICAM-1 in supported planar bilayers - a model for immunological synapse maturation. We found that reduction of MYH9 expression levels using Myh9 siRNA in proliferating mouse CD4(+) AND T cell receptor (TCR) transgenic T cells resulted in increased spreading area, failure to assemble the central and peripheral supramolecular activation clusters (cSMAC and pSMAC), and increased motility. Surprisingly, TCR microcluster speed was reduced marginally, however TCR microclusters dissipated prior to forming a cSMAC. TCR microclusters formed in the Myh9 siRNA-treated T cells showed reduced phosphorylation of the Src family kinase (SFK) activation loop and displayed reduced cytoplasmic calcium ion (Ca(2+)) elevation. In addition, Myh9 siRNA-treated cells displayed reduced phosphorylation of the Cas-L substrate domain - a force-dependent SFK substrate - which was observed in control siRNA-treated cells in foci throughout the immunological synapse except the cSMAC. Cas-L exhibited TCR ligation-dependent induction of phosphorylation. These results provide further evidence that T cell activation is modulated by intrinsic force-generating systems and can be viewed as a mechanically responsive process influenced by MYH9.
PMID: 22912631
ISSN: 1664-3224
CID: 175795

Cse1l is a negative regulator of CFTR-dependent fluid secretion

Bagnat, Michel; Navis, Adam; Herbstreith, Sara; Brand-Arzamendi, Koroboshka; Curado, Silvia; Gabriel, Sherif; Mostov, Keith; Huisken, Jan; Stainier, Didier Y R
Transport of chloride through the cystic fibrosis transmembrane conductance regulator (CFTR) channel is a key step in regulating fluid secretion in vertebrates [1, 2]. Loss of CFTR function leads to cystic fibrosis [1, 3, 4], a disease that affects the lungs, pancreas, liver, intestine, and vas deferens. Conversely, uncontrolled activation of the channel leads to increased fluid secretion and plays a major role in several diseases and conditions including cholera [5, 6] and other secretory diarrheas [7] as well as polycystic kidney disease [8-10]. Understanding how CFTR activity is regulated in vivo has been limited by the lack of a genetic model. Here, we used a forward genetic approach in zebrafish to uncover CFTR regulators. We report the identification, isolation, and characterization of a mutation in the zebrafish cse1l gene that leads to the sudden and dramatic expansion of the gut tube. We show that this phenotype results from a rapid accumulation of fluid due to the uncontrolled activation of the CFTR channel. Analyses in zebrafish larvae and mammalian cells indicate that Cse1l is a negative regulator of CFTR-dependent fluid secretion. This work demonstrates the importance of fluid homeostasis in development and establishes the zebrafish as a much-needed model system to study CFTR regulation in vivo.
PMID: 20933420
ISSN: 0960-9822
CID: 179385

deLiver'in regeneration: injury response and development

Curado, Silvia; Stainier, Didier Y R
Liver regeneration has traditionally been investigated in mammalian models. Recent technological developments in mouse genetics have greatly enhanced the resolving power of these studies. In addition, the zebrafish system has emerged as a complementary genetic system to study liver regeneration. One of the most promising attributes of the zebrafish system is its amenability to large-scale screens including genetic and chemical screens. Also, as our understanding of liver development is becoming more detailed, it is important to evaluate the commonalities and differences between organ development and regeneration.
PMID: 20665380
ISSN: 0272-8087
CID: 179386

The mitochondrial import gene tomm22 is specifically required for hepatocyte survival and provides a liver regeneration model

Curado, Silvia; Ober, Elke A; Walsh, Susan; Cortes-Hernandez, Paulina; Verkade, Heather; Koehler, Carla M; Stainier, Didier Y R
Understanding liver development should lead to greater insights into liver diseases and improve therapeutic strategies. In a forward genetic screen for genes regulating liver development in zebrafish, we identified a mutant--oliver--that exhibits liver-specific defects. In oliver mutants, the liver is specified, bile ducts form and hepatocytes differentiate. However, the hepatocytes die shortly after their differentiation, and thus the resulting mutant liver consists mainly of biliary tissue. We identified a mutation in the gene encoding translocase of the outer mitochondrial membrane 22 (Tomm22) as responsible for this phenotype. Mutations in tomm genes have been associated with mitochondrial dysfunction, but most studies on the effect of defective mitochondrial protein translocation have been carried out in cultured cells or unicellular organisms. Therefore, the tomm22 mutant represents an important vertebrate genetic model to study mitochondrial biology and hepatic mitochondrial diseases. We further found that the temporary knockdown of Tomm22 levels by morpholino antisense oligonucleotides causes a specific hepatocyte degeneration phenotype that is reversible: new hepatocytes repopulate the liver as Tomm22 recovers to wild-type levels. The specificity and reversibility of hepatocyte ablation after temporary knockdown of Tomm22 provides an additional model to study liver regeneration, under conditions where most hepatocytes have died. We used this regeneration model to analyze the signaling commonalities between hepatocyte development and regeneration.
PMID: 20483998
ISSN: 1754-8403
CID: 179387