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Zurakowski, David

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Zurakowski

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David

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Zurakowski, David
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    Posterior Tracheopexy for Severe Tracheomalacia Associated with Esophageal Atresia (EA): Primary Treatment at the Time of Initial EA Repair versus Secondary Treatment
    (Frontiers Media S.A., 2018) Shieh, Hester F.; Smithers, C. Jason; Hamilton, Thomas; Zurakowski, David; Visner, Gary; Manfredi, Michael A.; Baird, Christopher; Jennings, Russell
    Purpose We review outcomes of posterior tracheopexy for tracheomalacia in esophageal atresia (EA) patients, comparing primary treatment at the time of initial EA repair versus secondary treatment. Methods: All EA patients who underwent posterior tracheopexy from October 2012 to September 2016 were retrospectively reviewed. Clinical symptoms, tracheomalacia scores, and persistent airway intrusion were collected. Indication for posterior tracheopexy was the presence of clinical symptoms, in combination with severe tracheomalacia as identified on bronchoscopic evaluation, typically defined as coaptation in one or more regions of the trachea. Secondary cases were usually those with chronic respiratory symptoms who underwent bronchoscopic evaluation, whereas primary cases were those found to have severe tracheomalacia on routine preoperative dynamic tracheobronchoscopy at the time of initial EA repair. Results: A total of 118 patients underwent posterior tracheopexy: 18 (15%) primary versus 100 (85%) secondary cases. Median (interquartile range) age was 2 months (1–4 months) for primary (22% type C) and 18 months (8–40 months) for secondary (87% type C) cases (p < 0.001). There were statistically significant improvements in most clinical symptoms postoperatively for primary and secondary cases, with no significant differences in any postoperative symptoms between the two groups (p > 0.1). Total tracheomalacia scores improved significantly in primary (p = 0.013) and secondary (p < 0.001) cases. Multivariable Cox regression analysis indicated no differences in persistent airway intrusion requiring reoperation between primary and secondary tracheopexy adjusting for imbalances in age and EA type (p = 0.67). Conclusion: Posterior tracheopexy is effective in treating severe tracheomalacia with significant improvements in clinical symptoms and degree of airway collapse on bronchoscopy. With no significant differences in outcomes between primary and secondary treatment, posterior tracheopexy should be selectively considered at the time of initial EA repair.
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    Microstructural Alterations and Oligodendrocyte Dysmaturation in White Matter After Cardiopulmonary Bypass in a Juvenile Porcine Model
    (John Wiley and Sons Inc., 2017) Stinnett, Gary R.; Lin, Stephen; Korotcov, Alexandru V.; Korotcova, Ludmila; Morton, Paul D.; Ramachandra, Shruti D.; Pham, Angeline; Kumar, Sonali; Agematsu, Kota; Zurakowski, David; Wang, Paul C.; Jonas, Richard A.; Ishibashi, Nobuyuki
    Background: Newly developed white matter (WM) injury is common after cardiopulmonary bypass (CPB) in severe/complex congenital heart disease. Fractional anisotropy (FA) allows measurement of macroscopic organization of WM pathology but has rarely been applied after CPB. The aims of our animal study were to define CPB‐induced FA alterations and to determine correlations between these changes and cellular events after congenital heart disease surgery. Methods and Results: Normal porcine WM development was first assessed between 3 and 7 weeks of age: 3‐week‐old piglets were randomly assigned to 1 of 3 CPB‐induced insults. FA was analyzed in 31 WM structures. WM oligodendrocytes, astrocytes, and microglia were assessed immunohistologically. Normal porcine WM development resembles human WM development in early infancy. We found region‐specific WM vulnerability to insults associated with CPB. FA changes after CPB were also insult dependent. Within various WM areas, WM within the frontal cortex was susceptible, suggesting that FA in the frontal cortex should be a biomarker for WM injury after CPB. FA increases occur parallel to cellular processes of WM maturation during normal development; however, they are altered following surgery. CPB‐induced oligodendrocyte dysmaturation, astrogliosis, and microglial expansion affect these changes. FA enabled capturing CPB‐induced cellular events 4 weeks postoperatively. Regions most resilient to CPB‐induced FA reduction were those that maintained mature oligodendrocytes. Conclusions: Reducing alterations of oligodendrocyte development in the frontal cortex can be both a metric and a goal to improve neurodevelopmental impairment in the congenital heart disease population. Studies using this model can provide important data needed to better interpret human imaging studies.
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    Quantifying Temporomandibular Joint Synovitis in Children With Juvenile Idiopathic Arthritis
    (John Wiley and Sons Inc., 2016) Resnick, Cory; Vakilian, Pouya M.; Breen, Micheal; Zurakowski, David; Caruso, Paul; Henderson, Lauren; Nigrovic, Peter; Kaban, Leonard; Peacock, Zachary
    Objective: Juvenile idiopathic arthritis (JIA) frequently affects the temporomandibular joints (TMJs) and is often undetected by history, examination, and plain imaging. Qualitative assessment of gadolinium‐enhanced magnetic resonance images (MRIs) is currently the standard for diagnosis of TMJ synovitis associated with JIA. The purpose of this study is to apply a quantitative analysis of synovial enhancement to MRIs of patients with and without JIA to establish a disease threshold and sensitivity and specificity for the technique. Methods: This is a retrospective case–control study of children (age ≤16 years) who had MRIs with gadolinium including the TMJs. Subjects were divided into a JIA group and a control group. From a coronal T1‐weighted image, a ratio (enhancement ratio [ER]) of the average pixel intensity within three 0.2‐mm2 regions of interest (ROIs) in the TMJ synovium to that of a 50‐mm2 ROI of the longus capitis muscle was calculated. Receiver operating characteristic curves were used to determine the sensitivity and specificity. The inter‐ and intraexaminer reliability was evaluated with Bland‐Altman plots and 2‐way mixed, absolute agreement intraclass correlation coefficients. Results: There were 187 and 142 TMJs included in the JIA and control groups, respectively. An ER threshold of 1.55 had a sensitivity and specificity for detecting synovitis of 91% and 96%, respectively. The inter‐ and intraexaminer reliability was excellent. Conclusion: Calculating a ratio of pixel intensity between the TMJ synovium and the longus capitis muscle is a reliable way to quantify synovial enhancement. An ER of 1.55 differentiates normal TMJs from those affected by inflammatory arthritis.
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    Hypergammaglobulinemia in the pediatric population as a marker for underlying autoimmune disease: a retrospective cohort study
    (BioMed Central, 2013) Lo, Mindy; Zurakowski, David; Son, Mary; Sundel, Robert
    Background: The significance of hypergammaglobulinemia as a marker of immune activation is unknown, as a differential diagnosis for hypergammaglobulinemia in children has not been adequately established. The goal of this study was to identify conditions associated with hypergammaglobulinemia in children, with the hypothesis that elevated immunoglobulin levels may precede or predict the development of autoimmune conditions. Methods: We reviewed the medical records for all children with IgG level ≥2000 mg/dL treated at a tertiary care children’s hospital from January 1, 2000 through December 31, 2009. We compared clinical and laboratory features of these patients, and developed an algorithm to predict the likelihood of underlying autoimmunity based on these characteristics. Results: After excluding children who had received IVIG, a total of 442 patients with hypergammaglobulinemia were identified. Of these, nearly half had autoimmune conditions, most frequently systemic lupus erythematosus and lupus-related disorders. Autoimmune gastrointestinal disorders such as inflammatory bowel disease were also common. Infectious diseases were the next largest category of diseases, followed with much less frequency by malignant, drug-related, and other conditions. In comparison with non-autoimmune conditions, patients with autoimmune disease had higher IgG levels, lower white blood cell counts, lower hemoglobin values, and lower C-reactive protein (CRP) levels. Multivariable logistic regression confirmed that CRP (P = 0.002), white blood cell count (P < 0.001), hemoglobin (P = 0.015), and female gender (P < 0.001) are independent risk factors for autoimmune disease in patients with high IgG levels. Conclusions: In a cohort of pediatric patients at a tertiary care children’s hospital, hypergammaglobulinemia was most commonly associated with autoimmune diseases. In female patients with hypergammaglobulinemia, the presence of leukopenia, anemia, and normal CRP was 95% predictive of underlying autoimmune disease.
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    Pain hypersensitivity in juvenile idiopathic arthritis: a quantitative sensory testing study
    (BioMed Central, 2014) Cornelissen, Laura; Donado, Carolina; Kim, Joseph; Chiel, Laura; Zurakowski, David; Logan, Deirdre; Meier, Petra; Sethna, Navil; Blankenburg, Markus; Zernikow, Boris; Sundel, Robert; Berde, Charles
    Background: Juvenile Idiopathic Arthritis (JIA) is the most common cause of non-infectious joint inflammation in children. Synovial inflammation results in pain, swelling and stiffness. Animal and adult human studies indicate that localized joint-associated inflammation may produce generalized changes in pain sensitivity. The aim was to characterize pain sensitivity in children with JIA to mechanical and thermal stimulus modalities using quantitative sensory testing (QST) at an affected inflamed joint, and compare to children in clinical remission. Generalized hypersensitivity was evaluated by comparing QST measures at the thenar eminence between JIA and healthy control children. Methods: 60 children aged 7–17 years with JIA participated. QST assessed sensory detection threshold and pain threshold at two sites: (1) affected joint (clinically active or inactive), (2) contralateral thenar eminence. Joint site included finger, wrist, knee and ankle. Clinical status was measured using objective and subjective markers of disease severity. Questionnaires assessed pain intensity and frequency, functional disability, anxiety, pain catastrophization and fatigue. QST data collected from joints were compared within JIA patients: active vs. inactive inflammation; and data from the contralateral thenar eminence were compared between JIA and healthy control cohorts in Europe [EU, (n = 151)] and the US (n = 92). Statistical analyses were performed using Kruskal-Wallis with Dunn’s post-hoc comparison, Mann-Whitney or Fisher’s exact test, where appropriate. Results: Overall, children with JIA reported low pain scores and low degrees of functional disability. Sensory detection thresholds and pain thresholds were similar in “active” compared to “inactive” joints. Despite this, children with JIA had generalized hypersensitivity at the thenar eminence when compared to healthy children for pressure (vs. EU p < 0.001), light touch (vs. EU p < 0.001), cold (vs EU, p < 0.01; vs US, p < 0.001) and heat pain (vs EU, p < 0.05; vs US p < 0.001). Conclusions: JIA is associated with increased sensitivity to painful mechanical and thermal stimuli, even in absence of pain reports, or markers of disease activity. Future research investigating mechanisms underlying pain hypersensitivity in JIA is warranted; this will in turn guide pharmacologic and non-pharmacologic interventions to prevent or reverse these processes. Electronic supplementary material The online version of this article (doi:10.1186/1546-0096-12-39) contains supplementary material, which is available to authorized users.
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    A Modern Cohort of Duodenal Obstruction Patients: Predictors of Delayed Transition to Full Enteral Nutrition
    (Hindawi Publishing Corporation, 2014) Bairdain, Sigrid; Yu, David C.; Lien, Chueh; Khan, Faraz Ali; Pathak, Bhavana; Grabowski, Matthew J.; Zurakowski, David; Linden, Bradley C.
    Background:. A common site for neonatal intestinal obstruction is the duodenum. Delayed establishment of enteral nutritional autonomy continues to challenge surgeons and, since early institution of nutritional support is critical in postoperative newborns, identification of patients likely to require alternative nutritional support may improve their outcomes. Therefore, we aimed to investigate risk factors leading to delayed establishment of full enteral nutrition in these patients. Methods:. 87 patients who were surgically treated for intrinsic duodenal obstructions from 1998 to 2012 were reviewed. Variables were tested as potential risk factors. Median time to full enteral nutrition was estimated using the Kaplan-Meier method. Independent risk factors of delayed transition were identified using the multivariate Cox proportional hazards regression model. Results:. Median time to transition to full enteral nutrition was 12 days (interquartile range: 9–17 days). Multivariate Cox analysis identified three significant risk factors for delayed enteral nutrition: gestational age (GA) ≤ 35 weeks (P < .001), congenital heart disease (CHD) (P = .02), and malrotation (P = .03). Conclusions:. CHD and Prematurity are most commonly associated with delayed transition to full enteral nutrition. Thus, in these patients, supportive nutrition should strongly be considered pending enteral nutritional autonomy.
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    The Effect of Perioperative Ketorolac on the Clinical Failure Rate of Meniscal Repair
    (2014) Proffen, Benedikt; Nielson, Jason H.; Zurakowski, David; Micheli, Lyle; Curtis, Christine; Murray, Martha
    Background: There has been recent interest in the effect of nonsteroidal anti-inflammatory medications on musculoskeletal healing. No studies have yet addressed the effect of these medications on meniscal healing. Hypothesis The administration of ketorolac in the perioperative period will result in higher rates of meniscal repair clinical failure. Study design Cohort study; Level of evidence, 3. Methods: A total of 110 consecutive patients underwent meniscal repair at our institution between August 1998 and July 2001. Three patients were lost to follow-up, and the remaining 107 (mean age, 15.9 ± 4.4 years) had a minimum 5-year follow-up (mean follow-up, 5.5 years). Thirty-two patients (30%) received ketorolac perioperatively. The primary outcome measure was reoperation for continued symptoms of meniscal pathology. Asymptomatic patients were evaluated by the International Knee Documentation Committee (IKDC) Subjective Knee Form, Short Form–36 (SF-36) Health Survey, and Knee Outcome Osteoarthritis Score (KOOS). Results: Kaplan-Meier survivorship revealed no difference in reoperation rates with and without the administration of perioperative ketorolac (P = .95). There was an overall failure rate of 35% (37/107 patients), with a 34% failure rate in patients receiving ketorolac (11/32 patients). Multivariable Cox regression confirmed that age, duration of symptoms, meniscal tear type, fixation technique, concurrent anterior cruciate ligament repair, and ketorolac usage did not have an impact on the rate of failure (P > .05 for all; ketorolac use, P > .50). Female sex (P = .04) and medial location (P = .01) were predictive of an increased risk for reoperation. Conclusion: Failure of meniscal repair was not altered with the administration of perioperative ketorolac. Further work studying the effects of longer term anti-inflammatory use after meniscal repair is necessary before stating that this class of medications has no effect on meniscal healing. Clinical Relevance Results of this study suggest that nonsteroidal anti-inflammatory ketorolac can be administered perioperatively during a meniscal repair procedure to harness its benefits of decreased narcotic requirement, decreased pain, and shorter length of hospital stay without negatively influencing the long-term outcome of the surgery.
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    Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer
    (Impact Journals LLC, 2016) Brauner, Eran; Gunda, Viswanath; Borre, Pierre Vanden; Zurakowski, David; Kim, Yon Seon; Dennett, Kate Virginia; Amin, Salma; Freeman, Gordon; Parangi, Sareh
    The interaction of programmed cell death-1 and its ligand is widely studied in cancer. Monoclonal antibodies blocking these molecules have had great success but little is known about them in thyroid cancer. We investigated the role of PD-L1 in thyroid cancer with respect to BRAF mutation and MAP kinase pathway activity and the effect of anti PD-L1 antibody therapy on tumor regression and intra-tumoral immune response alone or in combination with BRAF inhibitor (BRAFi). BRAFV600E cells showed significantly higher baseline expression of PD-L1 at mRNA and protein levels compared to BRAFWT cells. MEK inhibitor treatment resulted in a decrease of PD-L1 expression across all cell lines. BRAFi treatment decreased PD-L1 expression in BRAFV600E cells, but paradoxically increased its expression in BRAFWT cells. BRAFV600E mutated patients samples had a higher level of PD-L1 mRNA compared to BRAFWT (p=0.015). Immunocompetent mice (B6129SF1/J) implanted with syngeneic 3747 BRAFV600E/WT P53−/− murine tumor cells were randomized to control, PLX4720, anti PD-L1 antibody and their combination. In this model of aggressive thyroid cancer, control tumor volume reached 782.3±174.6mm3 at two weeks. The combination dramatically reduced tumor volume to 147.3±60.8, compared to PLX4720 (439.3±188.4 mm3, P=0.023) or PD-L1 antibody (716.7±62.1, P<0.001) alone. Immunohistochemistry analysis revealed intense CD8+ CTL infiltration and cytotoxicity and favorable CD8+:Treg ratio compared to each individual treatment. Our results show anti PD-L1 treatment potentiates the effect of BRAFi on tumor regression and intensifies anti tumor immune response in an immunocompetent model of ATC. Clinical trials of this therapeutic combination may be of benefit in patients with ATC.
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    Medication use in juvenile uveitis patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry
    (BioMed Central, 2016) Henderson, Lauren; Zurakowski, David; Angeles-Han, Sheila T.; Lasky, Andrew; Rabinovich, C. Egla; Lo, Mindy
    Background: There is not yet a commonly accepted, standardized approach in the treatment of juvenile idiopathic uveitis when initial steroid therapy is insufficient. We sought to assess current practice patterns within a large cohort of children with juvenile uveitis. Methods: This is a cross-sectional cohort study of patients with uveitis enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRAnet) registry. Clinical information including, demographic information, presenting features, disease complications, and medications were collected. Chi-square and Fisher’s exact tests were used to assess for associations between medications and clinical characteristics. Results: Ninety-two children with idiopathic and 656 with juvenile idiopathic arthritis (JIA)-associated uveitis were identified. Indication (arthritis or uveitis) for medication use was not available for JIA patients; therefore, detailed analysis was limited to children with idiopathic uveitis. In this group, 94 % had received systemic steroids. Methotrexate (MTX) was used in 76 % of patients, with oral and subcutaneous forms given at similar rates. In multivariable analysis, non-Caucasians were more likely to be treated initially with subcutaneous MTX (P = 0.003). Of the 53 % of patients treated with a biologic DMARD, all received a tumor necrosis factor (TNF) inhibitor. TNF inhibitor use was associated with a higher frequency of cataracts (52 % vs 21 %; P = 0.001) and antinuclear antibody positivity (49 % vs 29 %; P = 0.04), although overall complication rates were not higher in these patients. Conclusion: Among idiopathic uveitis patients enrolled in the CARRAnet registry, MTX was the most commonly used DMARD, with subcutaneous and oral forms equally favored. Patients who received a TNF inhibitor were more likely to be ANA positive and have cataracts. Electronic supplementary material The online version of this article (doi:10.1186/s12969-016-0069-5) contains supplementary material, which is available to authorized users.
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    A Phase 1, Dose-escalation, Double-blind, Block-randomized, Controlled Trial of Safety and Efficacy of Neosaxitoxin Alone and in Combination with 0.2% Bupivacaine, with and without Epinephrine, for Cutaneous Anesthesia
    (Ovid Technologies (Wolters Kluwer Health), 2015) Lobo, Kimberly; Donado, Carolina; Cornelissen, Laura; Kim, Joseph; Ortiz, Rebeca; Peake, Roy; Kellogg, Mark; Alexander, Mark; Zurakowski, David; Kurgansky, Katherine E.; Peyton, James; Bilge, Aykut; Boretsky, Karen; McCann, Mary Ellen; Berde, Charles; Cravero, Joseph
    BACKGROUND: Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans. Under a Food and Drug Administration-approved phase 1 Investigational New Drug trial, the authors evaluated safety and efficacy of NeoSTX alone and combined with 0.2% bupivacaine (Bup) with and without epinephrine. METHODS: The authors conducted a double-blind, randomized, controlled trial involving healthy male volunteers aged 18 to 35 yr receiving two 10-ml subcutaneous injections. Control sites received Bup. In part 1, active sites received (1) 5 to 40 μg NeoSTX+Saline (NeoSTX-Saline), (2) 5 to 40 μg NeoSTX+Bup (NeoSTX-Bup), or (3) placebo (Saline). In part 2, active sites received 10 or 30 μg NeoSTX+Bup+Epinephrine (NeoSTX-Bup-Epi) or placebo. Primary outcome measures were safety and adverse events associated with NeoSTX. Secondary outcomes included clinical biochemistry, NeoSTX pharmacokinetics, and cutaneous hypoesthesia. RESULTS: A total of 84 subjects were randomized and completed the two-part trial with no serious adverse events or clinically significant physiologic impairments. Perioral numbness and tingling increased with NeoSTX dose for NeoSTX-Saline and NeoSTX-Bup. All symptoms resolved without intervention. NeoSTX-Bup-Epi dramatically reduced symptoms compared with other NeoSTX combinations (tingling: 0 vs. 70%, P = 0.004; numbness: 0 vs. 60%, P = 0.013) at the same dose. Mean peak plasma NeoSTX concentration for NeoSTX-Bup-Epi was reduced at least two-fold compared with NeoSTX-Saline and NeoSTX-Bup (67 ± 14, 134 ± 63, and 164 ± 81 pg/ml, respectively; P = 0.016). NeoSTX-Bup showed prolonged cutaneous block duration compared with Bup, NeoSTX-Saline, or placebo, at all doses. Median time to near-complete recovery for 10 μg NeoSTX-Bup-Epi was almost five-fold longer compared with Bup (50 vs. 10 h, P = 0.007). CONCLUSION: NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.