• Early administration of terbutaline in severe pediatric asthma may reduce incidence of acute respiratory failure.

  Doymaz, Sule; Schneider, James; Sagy, Mayer (2014-01-25)

  Background: Severe pediatric asthma, if not immediately and aggressively treated, may progress to acute respiratory failure requiring mechanical ventilation in the pediatric intensive care unit (PICU). Intravenous (IV) terbutaline, a β2 agonist, is dispensed when the initial treatment does not improve the clinical condition. Objective: To investigate the influence of early initiation of IV terbutaline on the incidence of acute respiratory failure requiring mechanical ventilation in severe pediatric asthma. Methods: A retrospective chart review was conducted of 120 subjects (35 patients from an outside hospital emergency department [ED] with late start of terbutaline and 85 patients from the authors' hospital ED with early initiation of IV terbutaline) admitted to the PICU with severe asthma treated with continuous IV terbutaline. Responses to terbutaline treatment and outcomes were evaluated. Results: Patients transported from outlying hospital EDs had shorter pre-PICU mean durations of IV terbutaline than those transferred from the authors' ED (0.69 ± 1.38 and 2.91 ± 2.47 hours, respectively, P = .001). Twenty-one of 35 patients (60%) from outlying EDs required mechanical ventilation compared with 14 of 85 patients (16%) from the authors' ED (P = .001). Durations of pre-PICU terbutaline infusion for patients requiring mechanical ventilation were significantly shorter than those with no such requirement (P = .015). Conclusion: The results of the present study, conducted in the largest number of subjects to date, suggest that early administration of continuous terbutaline in the ED may decrease acute respiratory failure and the need for mechanical respiratory (invasive and noninvasive) support in severe pediatric asthma.
• Risk factors associated with intracranial hemorrhage in neonates with persistent pulmonary hypertension on ECMO.

  Doymaz, Sule; Zinger, Marcia; Sweberg, Todd (2015-02-11)

  Background: Up to 40% of infants with persistent pulmonary hypertension (PPHN) remains refractory to conventional therapies, and extracorporeal membrane oxygenation (ECMO) is offered as an effective support for this group. However, ECMO is a highly invasive and risky procedure with devastating complications such as intracranial hemorrhage (ICH). In this study, we aimed to determine the risk factors for ICH in infants with PPHN. Methods: A case-control study of patients admitted to the pediatric intensive care unit (PICU) with PPHN requiring ECMO support was conducted. The study was carried out at a 25-bed PICU in large urban tertiary care children's hospital. A total number of 32 subjects were studied. Patients with and without ICH during ECMO were evaluated for activated clotting time (ACT), heparin dosing, platelet count, coagulation profile such as activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR), fibrinogen level, vital signs including heart rate and mean arterial pressure (MAP), transfusion history, gestational age, and severity of pre-ECMO illness as possible risk factors. Results: Low fibrinogen level (115 ± 13 mg/dl) and low platelet counts (37.4 ± 18.3 Thousand/μl) were associated with higher incidence of ICH (p = 0.009 and p = 0.005, respectively). Elevated MAP (69 ± 4.34 mmHg) was also noticed in ICH patients (p = 0.006). Conclusions: Results demonstrated that low fibrinogen level and low platelet count were associated with ICH in PPHN patients on ECMO. While on ECMO support, maintaining fibrinogen and platelet counts within normal ranges seems crucial to prevent ICH in PPHN patients. This is the first report identifying low fibrinogen level among the risk factors for ICH in infants with PPHN on ECMO support.
• How Prepared Are Pediatric Residents for Pediatric Emergencies: Is Pediatric Advanced Life Support Certification Every 2 Years Adequate?

  Doymaz, Sule; Rizvi, Munaza; Orsi, Marguerite; Giambruno, Clara (2019-09-16)

  Objectives. We assessed pediatric residents' retention of knowledge and clinical skills according to the time since their last American Heart Association Pediatric Advanced Life Support (AHA PALS) certification. Methods. Sixty-four pediatric residents were recruited and divided into 3 groups based on the time since their last PALS certification, as follows: group 1, 0 to 8 months; group 2, 9 to 16 months, and group 3, 17 to 24 months. Residents' knowledge was tested using 10 multiple-choice AHA PALS pretest questions and their clinical skills performance was assessed with simulation mock code scenarios using 2 different AHA PALS checklists, and mean scores were calculated for the 3 groups. Differences in the test scores and overall clinical skill performances among the 3 groups were analyzed using analyses of variance, χ2 tests, and Jonckheere-Terpstra tests. Statistical significance was set at P < .05. Results. The pediatric residents' mean overall clinical skills performance scores declined within the first 8 months after their last AHA PALS certification date and continued to decrease over time (87%, 82.6%, and 77.4% for groups 1, 2, and 3, respectively; P = .048). Residents' multiple-choice test scores declined in all 3 groups, but the scores were not significantly different. Conclusions. Residents' clinical skills performance declined within the first 8 months after PALS certification and continued to decline as the time from the last certification increased. Using mock code simulations and reinforcing AHA PALS guidelines during pediatric residency deserve further evaluation.
• Clinical Manifestations and Outcomes of Critically Ill Children and Adolescents with Coronavirus Disease 2019 in New York City.

  Derespina, Kim R; Kaushik, Shubhi; Plichta, Anna; Conway, Edward E; Bercow, Asher; Choi, Jaeun; Eisenberg, Ruth; Gillen, Jennifer; Sen, Anita I; Hennigan, Claire M; et al. (2020-07-16)

  Objectives: To describe the clinical manifestations and outcomes of critically ill children with coronavirus disease-19 (COVID-19) in New York City. Study design: Retrospective observational study of children 1 month to 21 years admitted March 14 to May 2, 2020, to 9 New York City pediatric intensive care units (PICUs) with severe acute respiratory syndrome coronavirus 2 infection. Results: Of 70 children admitted to PICUs, median age was 15 (IQR 9, 19) years; 61.4% male; 38.6% Hispanic; 32.9% black; and 74.3% with comorbidities. Fever (72.9%) and cough (71.4%) were the common presenting symptoms. Twelve patients (17%) met severe sepsis criteria; 14 (20%) required vasopressor support; 21 (30%) developed acute respiratory distress syndrome (ARDS); 9 (12.9%) met acute kidney injury criteria; 1 (1.4%) required renal-replacement therapy, and 2 (2.8%) had cardiac arrest. For treatment, 27 (38.6%) patients received hydroxychloroquine; 13 (18.6%) remdesivir; 23 (32.9%) corticosteroids; 3 (4.3%) tocilizumab; and 1 (1.4%) anakinra; no patient was given immunoglobulin or convalescent plasma. Forty-nine (70%) patients required respiratory support: 14 (20.0%) noninvasive mechanical ventilation, 20 (28.6%) invasive mechanical ventilation (IMV), 7 (10%) prone position, 2 (2.8%) inhaled nitric oxide, and 1 (1.4%) extracorporeal membrane oxygenation. Nine (45%) of the 20 patients requiring IMV were extubated by day 14 with median IMV duration of 218 (IQR 79, 310.4) hours. Presence of ARDS was significantly associated with duration of PICU and hospital stay, and lower probability of PICU and hospital discharge at hospital day 14 (P < .05 for all). Conclusions: Critically ill children with COVID-19 predominantly are adolescents, have comorbidities, and require some form of respiratory support. The presence of ARDS is significantly associated with prolonged PICU and hospital stay.
• Multisystem Inflammatory Syndrome in U.S. Children and Adolescents.

  Feldstein, Leora R; Rose, Erica B; Horwitz, Steven M; Collins, Jennifer P; Newhams, Margaret M; Son, Mary Beth F; Newburger, Jane W; Kleinman, Lawrence C; Heidemann, Sabrina M; Martin, Amarilis A; et al. (2020-06-29)

  Background: Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. Methods: We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. Results: We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki's disease-like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). Conclusions: Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.).
• Improving the Performance of Residents in Pediatric Resuscitation with Frequent Simulated Codes.

  Doymaz, Sule; Rizvi, Munaza; Giambruno, Clara (2020-10-30)

  Aim. Exposure to real codes during pediatric residency training is scarce. Consequently, experiencing mock codes scenarios can provide an opportunity to increase residents' confidence and knowledge in managing pediatric emergencies. Hypothesis. Pediatric senior residents perform better as code team leaders if they are exposed to frequent mock codes. Material and Methods. Forty-three pediatric senior residents (postgraduate year [PGY] two and three) participated in the study. Team leader performance was assessed utilizing the Team Emergency Assessment Measure (TEAM) scoring. Residents' team leadership performance was assessed before and 6 months after the implementation of weekly mock codes. Results. Pediatric residents' team leadership performance in mock codes improved after exposure to weekly practice mock code sessions (71.93 ± 18.50 vs 81.44 ± 11.84, P = 0.01). Conclusion. Increasing the frequency of mock code sessions during residency training led to an improvement in code team leadership performance in pediatric senior residents.
• Characteristics and Outcomes of US Children and Adolescents With Multisystem Inflammatory Syndrome in Children (MIS-C) Compared With Severe Acute COVID-19.

  Feldstein, Leora R; Tenforde, Mark W; Friedman, Kevin G; Newhams, Margaret; Rose, Erica Billig; Dapul, Heda; Soma, Vijaya L; Maddux, Aline B; Mourani, Peter M; Bowens, Cindy; et al.

  Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). Setting, design, and participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. Exposure: SARS-CoV-2. Main outcomes and measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/μL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days. Conclusions and relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.
• Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome.

  LaRovere, Kerri L; Riggs, Becky J; Poussaint, Tina Y; Young, Cameron C; Newhams, Margaret M; Maamari, Mia; Walker, Tracie C; Singh, Aalok R; Dapul, Heda; Hobbs, Charlotte V; et al.

  Importance: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. Objective: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. Setting, design, and participants: Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features. Exposures: Severe acute respiratory syndrome coronavirus 2. Main outcomes and measures: Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge. Results: Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19-related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died. Conclusions and relevance: In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.
• Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes.

  Son, Mary Beth F; Murray, Nancy; Friedman, Kevin; Young, Cameron C; Newhams, Margaret M; Feldstein, Leora R; Loftis, Laura L; Tarquinio, Keiko M; Singh, Aalok R; Heidemann, Sabrina M; et al. (2021-06-16)

  Background: The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. Methods: We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. Results: A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score-matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score-matched analysis. Conclusions: Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.).
• Data-driven clustering identifies features distinguishing multisystem inflammatory syndrome from acute COVID-19 in children and adolescents.

  Geva, Alon; Patel, Manish M; Newhams, Margaret M; Young, Cameron C; Son, Mary Beth F; Kong, Michele; Maddux, Aline B; Hall, Mark W; Riggs, Becky J; Singh, Aalok R; et al. (2021-08-31)

  Background: Multisystem inflammatory syndrome in children (MIS-C) consensus criteria were designed for maximal sensitivity and therefore capture patients with acute COVID-19 pneumonia. Methods: We performed unsupervised clustering on data from 1,526 patients (684 labeled MIS-C by clinicians) <21 years old hospitalized with COVID-19-related illness admitted between 15 March 2020 and 31 December 2020. We compared prevalence of assigned MIS-C labels and clinical features among clusters, followed by recursive feature elimination to identify characteristics of potentially misclassified MIS-C-labeled patients. Findings: Of 94 clinical features tested, 46 were retained for clustering. Cluster 1 patients (N = 498; 92% labeled MIS-C) were mostly previously healthy (71%), with mean age 7·2 ± 0·4 years, predominant cardiovascular (77%) and/or mucocutaneous (82%) involvement, high inflammatory biomarkers, and mostly SARS-CoV-2 PCR negative (60%). Cluster 2 patients (N = 445; 27% labeled MIS-C) frequently had pre-existing conditions (79%, with 39% respiratory), were similarly 7·4 ± 2·1 years old, and commonly had chest radiograph infiltrates (79%) and positive PCR testing (90%). Cluster 3 patients (N = 583; 19% labeled MIS-C) were younger (2·8 ± 2·0 y), PCR positive (86%), with less inflammation. Radiographic findings of pulmonary infiltrates and positive SARS-CoV-2 PCR accurately distinguished cluster 2 MIS-C labeled patients from cluster 1 patients. Interpretation: Using a data driven, unsupervised approach, we identified features that cluster patients into a group with high likelihood of having MIS-C. Other features identified a cluster of patients more likely to have acute severe COVID-19 pulmonary disease, and patients in this cluster labeled by clinicians as MIS-C may be misclassified. These data driven phenotypes may help refine the diagnosis of MIS-C.
• Genes regulating levels of ω-3 long-chain polyunsaturated fatty acids are associated with alcohol use disorder and consumption, and broader externalizing behavior in humans.

  Aliev, Fazil; Barr, Peter B; Davies, Andrew G; Dick, Danielle M; Bettinger, Jill C (2022-08-07)

  Background: Individual variation in the physiological response to alcohol is predictive of an individual's likelihood to develop alcohol use disorder (AUD). Evidence from diverse model organisms indicates that the levels of long-chain polyunsaturated omega-3 fatty acids (ω-3 LC-PUFAs) can modulate the behavioral response to ethanol and therefore may impact the propensity to develop AUD. While most ω-3 LC-PUFAs come from diet, humans can produce these fatty acids from shorter chain precursors through a series of enzymatic steps. Natural variation in the genes encoding these enzymes has been shown to affect ω-3 LC-PUFA levels. We hypothesized that variation in these genes could contribute to the susceptibility to develop AUD. Methods: We identified nine genes (FADS1, FADS2, FADS3, ELOVL2, GCKR, ELOVL1, ACOX1, APOE, and PPARA) that are required to generate ω-3 LC-PUFAs and/or have been shown or predicted to affect ω-3 LC-PUFA levels. Using both set-based and gene-based analyses we examined their association with AUD and two AUD-related phenotypes, alcohol consumption, and an externalizing phenotype. Results: We found that the set of nine genes is associated with all three phenotypes. When examined individually, GCKR, FADS2, and ACOX1 showed significant association signals with alcohol consumption. GCKR was significantly associated with AUD. ELOVL1 and APOE were associated with externalizing. Conclusions: Taken together with observations that dietary ω-3 LC-PUFAs can affect ethanol-related phenotypes, this work suggests that these fatty acids provide a link between the environmental and genetic influences on the risk of developing AUD.
• Principal Component Analysis Reduces Collider Bias in Polygenic Score Effect Size Estimation.

  Thomas, Nathaniel S; Barr, Peter; Aliev, Fazil; Stephenson, Mallory; Kuo, Sally I-Chun; Chan, Grace; Dick, Danielle M; Edenberg, Howard J; Hesselbrock, Victor; Kamarajan, Chella; et al. (2022-06-08)

  In this study, we test principal component analysis (PCA) of measured confounders as a method to reduce collider bias in polygenic association models. We present results from simulations and application of the method in the Collaborative Study of the Genetics of Alcoholism (COGA) sample with a polygenic score for alcohol problems, DSM-5 alcohol use disorder as the target phenotype, and two collider variables: tobacco use and educational attainment. Simulation results suggest that assumptions regarding the correlation structure and availability of measured confounders are complementary, such that meeting one assumption relaxes the other. Application of the method in COGA shows that PC covariates reduce collider bias when tobacco use is used as the collider variable. Application of this method may improve PRS effect size estimation in some cases by reducing the effect of collider bias, making efficient use of data resources that are available in many studies.
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  Structural Model of the Extracellular Assembly of the TCR-CD3 Complex.

  Natarajan, Aswin; Nadarajah, Vidushan; Felsovalyi, Klara; Wang, Wenjuan; Jeyachandran, Vivian R; Wasson, Riley A; Cardozo, Timothy; Bracken, Clay; Krogsgaard, Michelle (2016-03-17)

  Antigen recognition of peptide-major histocompatibility complexes (pMHCs) by T cells, a key step in initiating adaptive immune responses, is performed by the T cell receptor (TCR) bound to CD3 heterodimers. However, the biophysical basis of the transmission of TCR-CD3 extracellular interaction into a productive intracellular signaling sequence remains incomplete. Here we used nuclear magnetic resonance (NMR) spectroscopy combined with mutational analysis and computational docking to derive a structural model of the extracellular TCR-CD3 assembly. In the inactivated state, CD3γε interacts with the helix 3 and helix 4-F strand regions of the TCR Cβ subunit, whereas CD3δε interacts with the F and C strand regions of the TCR Cα subunit in this model, placing the CD3 subunits on opposing sides of the TCR. This work identifies the molecular contacts between the TCR and CD3 subunits, identifying a physical basis for transmitting an activating signal through the complex.
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  Limb Salvage Versus Amputation in Conventional Appendicular Osteosarcoma: a Systematic Review.

  Jauregui, Julio J; Nadarajah, Vidushan; Munn, Joseph; Pivec, Robert; Kapadia, Bhaveen H; Lerman, Daniel M; Maheshwari, Aditya V (2018-01-20)

  The overall survivorship in patients with appendicular osteosarcoma has increased in the past few decades. However, controversies and questions about performing an amputation or a limb salvage procedure still remain. Using three peer-reviewed library databases, a systematic review of the literature was performed to evaluate all studies that have evaluated the outcomes of appendicular osteosarcoma, either with limb salvage or amputation. The mean 5-year overall survivorship was 62% for salvage and 58% for amputation (p > 0.05). At mean 6-year follow-up, the local recurrence rates were 8.2% for salvage and 3.0% for amputation (p > 0.05). Additionally, at mean 6-year follow-up, the rate for metastasis was 33% for salvage and 38% for amputation (p > 0.05). The revision rates were higher with salvage (31 vs. 28%), and there were more complications in the salvage groups (52 vs. 34%; p > 0.05). Despite the heterogeneity of studies available for review, we observed similar survival rates between the two procedures. Although there was no significant statistical difference between rates of recurrence and metastasis, the local recurrence rate and risk of complications were higher for limb salvage as compared to amputation. Cosmetic satisfaction is often higher with limb salvage, whereas long-term expense is higher with amputation. Overall, current literature supports limb salvage procedures when wide surgical margins can be achieved while still retaining a functional limb.
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  Patients' Use and Perception of Internet-Based Orthopaedic Sports Medicine Resources.

  Koenig, Scott; Nadarajah, Vidushan; Smuda, Michael P; Meredith, Sean; Packer, Jonathan D; Henn, R Frank (2018-09-20)

  Background: Current research is sparse regarding how patients with orthopaedic injuries perceive and use internet-based information resources. Hypothesis: The majority of patients use the internet to research their orthopaedic condition and are receptive to guidance from their provider. Study design: Cross-sectional study. Methods: A total of 213 patients attending a sports medicine clinic on the East Coast of the United States were asked to complete a questionnaire regarding their use of internet-based information. Data from 185 patients were available for analysis. Bivariate and multivariate statistical analyses were used to determine the significance of identified associations. Results: Overall, 54% of patients used the internet to find information about their orthopaedic condition prior to their consultation. A higher percentage of internet users were women (P = .01), were white (P = .03), and had internet access at home (P = .02). Multivariable analysis found home internet access to be the only significant independent factor predictive of patients using internet-based information sources (P < .01). The majority of patients (61%) were neutral toward orthopaedic information found online, and only 32% of patients trusted the orthopaedic information they found online. The majority of patients (83%) reported they would be receptive to providers' guidance on which internet resources to use. Conclusion: Only half of patients use the internet to research their orthopaedic condition. Most patients were either neutral toward or did not trust the internet-based information that they found and may forgo internet sources altogether. To help patients avoid misleading information, sports medicine providers should understand how patients are using the internet and guide patients in selecting high-quality, peer-reviewed sources of information. Doing so allows physicians to proactively educate their patients even after the clinic visit.
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  Knee dislocation with popliteal artery disruption: A nationwide analysis from 2005 to 2013.

  Naziri, Qais; Beyer, George A; Shah, Neil V; Solow, Maximillian; Hayden, Andrew J; Nadarajah, Vidushan; Ho, Derek; Newman, Jared M; Boylan, Matthew R; Basu, Niladri N; et al. (2018-08-16)

  Objective: Few have compared short-term outcomes following knee dislocations with or without concomitant popliteal artery disruption (PAD). Methods: The Nationwide Inpatient Sample was used to identify 2175 patients admitted for knee dislocation from 2005 to 2013 (concomitant PAD: n = 210/9.7%; without: n = 1965/90.3%). Results: Patients with PAD were younger, more often male, Black and Hispanic, and with Medicaid (all p ≤ 0.013). PADs were associated with 11.0-times higher odds of increased LOS (95%CI, 6.6-18.4) and 2.8-times higher odds of experiencing any complication (95%CI, 2.03-3.92). Female sex was a protective factor against increased LOS, (OR = 0.65; 95%CI, 0.48-0.88). Conclusion: High suspicion index should be maintained for concomitant vascular injuries following knee dislocations.
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  Preoperative expectations and early postoperative met expectations of extremity orthopaedic surgery.

  Henry, Leah E; Aneizi, Ali; Nadarajah, Vidushan; Sajak, Patrick Mj; Stevens, Kali N; Zhan, Min; Gilotra, Mohit N; Packer, Jonathan D; Henn, R Frank (2020-06-16)

  Background: Preoperative patient expectations and met expectations are likely associated with the outcome of treatment. However, there is a lack of data regarding the preoperative expectations and early postoperative met expectations of patients undergoing extremity orthopaedic surgery. The purpose of this study was to identify the predictors of early postoperative met expectations in a cohort of patients undergoing extremity orthopaedic surgery and to assess the relationship between patient expectations and patient-reported outcome (PRO) measures. We hypothesized that patients with higher preoperative expectation scores and higher postoperative met expectation scores would have better early postoperative outcomes. Methods: Four hundred thirty-five patients age seventeen and older who underwent extremity orthopaedic surgery at one institution were prospectively enrolled in this study. Each patient completed a preoperative questionnaire that included an assessment of demographics, pain, function, general health, treatment expectations, activity level, and Patient-Reported Outcome Measurement Information System (PROMIS) computer adaptive testing. Expectations were evaluated using the Expectations Domain of the Musculoskeletal Outcomes Data Evaluation and Management System (MODEMS) questionnaire. Patients completed a follow-up questionnaire two weeks after surgery that also assessed MODEMS met expectations and satisfaction (Surgical Satisfaction Questionnaire (SSQ-8)). Results: The mean preoperative expectation score was 86.95 ± 16.59, and the mean postoperative met expectation score was 55.02 ± 27.63 (0-100 scale with 100 representing the highest level of expectations). Greater met expectations were significantly associated with white race (p = 0.025), college degree (p = 0.011), and higher income (p = 0.002). Greater met expectations were also significantly associated with greater postoperative physical function, social satisfaction, activity level, and subjective improvement, as well as lower pain interference, joint pain, body pain, fatigue, anxiety, and depression (p < 0.01 for each). Multivariable analysis results found that less postoperative joint pain and greater postoperative social satisfaction, improvement, and physical function were all significant independent predictors of greater met expectations at two weeks postoperative (p < 0.01 for each). Conclusion: Greater preoperative expectations are associated with better activity and less pain two weeks after surgery. Met expectations of extremity orthopaedic surgery were associated with postoperative physical function, social satisfaction, activity, pain, anxiety, depression, and subjective improvement. These results may have implications for preoperative counseling and risk factor modification.
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  Early patient satisfaction following orthopaedic surgery.

  Howard, Bailey; Aneizi, Ali; Nadarajah, Vidushan; Sajak, Patrick M J; Ventimiglia, Dominic J; Burt, Cameran I; Zhan, Min; Akabudike, Ngozi M; Henn, R Frank (2020-06-27)

  Background: The healthcare industry is shifting its focus from traditional clinical outcome measures to patient satisfaction metrics. This change has caused orthopaedic surgeons to become increasingly interested in factors influencing patient satisfaction, which would allow them to potentially modify these factors in an effort to increase postoperative satisfaction. The objective of this study was to identify factors associated with patient satisfaction two weeks following extremity orthopaedic surgery. Methods: Patients completed questionnaires preoperatively to assess demographics, activity, pain, expectations, and Patient-Reported Outcomes Measurement Information System (PROMIS) computer adaptive testing for Physical Function, Pain Interference, Social Satisfaction, Depression, Anxiety, and Fatigue. Two weeks after their operation, patients completed the same questionnaires in addition to an Improvement Survey and Met Expectations. Satisfaction was assessed with the Surgical Satisfaction Questionnaire. Results: Greater surgical satisfaction two weeks following orthopaedic surgery was associated with higher education, alcohol use, better scores on all PROMIS domains at baseline and two weeks, greater activity levels at baseline and two weeks, less bodily pain at baseline and two weeks, less pain in the surgical site at two weeks, greater met expectations, and greater improvement (p < 0.05). Conclusion: This study provides important information about patient satisfaction two weeks after orthopaedic surgery.
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  Predictors of early postoperative pain interference following orthopaedic surgery.

  Kator, Jamie; Aneizi, Ali; Nadarajah, Vidushan; Sajak, Patrick M J; Zhan, Min; Gilotra, Mohit N; Akabudike, Ngozi M; Packer, Jonathan D; Henn, R Frank (2020-11-13)

  Introduction: Despite the increasing incidence of orthopaedic surgeries, there is a lack of data reporting on patient experience and recovery following surgery. As such, there is a need to better characterize the natural history of pain interference (PI) after orthopaedic surgery to better manage patients' expectations and recovery. Purpose: To identify factors associated with greater pain interference two weeks following orthopaedic surgery. Methods: All patients undergoing elective outpatient orthopaedic surgery at a single urban academic institution were evaluated preoperatively from August 2016 to March 2018. Patients completed a baseline assessment consisting of demographic information, PROMIS computer adaptive testing in 6 domains including Pain Interference (PI), Physical Function, Social Satisfaction, Fatigue, Anxiety, and Depression. Two weeks following surgery, patients completed the same questionnaires along with assessments of Improvement and Satisfaction. Bivariate and multivariable regression analyses were performed. Categorical data was compared with ANOVA and continuous data was compared with Spearman's correlation coefficient (rs). Results: 435 patients (age = 41.1 ± 15.7, 47% female) were studied. Mean PI was 60.1 ± 7.0 prior to surgery and 61.7 ± 7.6 at 2 weeks postoperative. Worse 2 week PROMIS PI was associated with lower extremity surgery, prior surgery on the joint, preoperative opioid use, depression, lower income, lower education, and higher ASA score (p < 0.05). Better 2 week PROMIS PI was correlated with better baseline and better 2 week scores on all outcome measures. Multivariable analysis demonstrated that lower extremity surgery, worse preoperative pain scores, and worse preoperative pain interference were independent predictors of worse pain interference after surgery. Conclusion: Early postoperative pain interference is associated with function, demographic, and psychosocial factors.
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  Management of irreparable massive rotator cuff tears: a systematic review and meta-analysis of patient-reported outcomes, reoperation rates, and treatment response.

  Kovacevic, David; Suriani, Robert J; Grawe, Brian M; Yian, Edward H; Gilotra, Mohit N; Hasan, S Ashfaq; Srikumaran, Umasuthan; Hasan, Samer S; Cuomo, Frances; Burks, Robert T; et al. (2020-08-04)

  Background: There is no consensus on the treatment of irreparable massive rotator cuff tears. The goal of this systematic review and meta-analysis was to (1) compare patient-reported outcome scores, (2) define failure and reoperation rates, and (3) quantify the magnitude of patient response across treatment strategies. Methods: The MEDLINE, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and Scopus databases were searched for studies including physical therapy and operative treatment of massive rotator cuff tears. The criteria of the Methodological Index for Non-randomized Studies were used to assess study quality. Primary outcome measures were patient-reported outcome scores as well as failure, complication, and reoperation rates. To quantify patient response to treatment, we compared changes in the Constant-Murley score and American Shoulder and Elbow Surgeons (ASES) score with previously reported minimal clinically important difference (MCID) thresholds. Results: No level I or II studies that met the inclusion and exclusion criteria were found. Physical therapy was associated with a 30% failure rate among the included patients, and another 30% went on to undergo surgery. Partial repair was associated with a 45% retear rate and 10% reoperation rate. Only graft interposition was associated with a weighted average change that exceeded the MCID for both the Constant-Murley score and ASES score. Latissimus tendon transfer techniques using humeral bone tunnel fixation were associated with a 77% failure rate. Superior capsular reconstruction with fascia lata autograft was associated with a weighted average change that exceeded the MCID for the ASES score. Reverse arthroplasty was associated with a 10% prosthesis failure rate and 8% reoperation rate. Conclusion: There is a lack of high-quality comparative studies to guide treatment recommendations. Compared with surgery, physical therapy is associated with less improvement in perceived functional outcomes and a higher clinical failure rate.

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