Development of a Deep Learning Model for Retinal Hemorrhage Detection on Head Computed Tomography in Young Children.

Importance: Abusive head trauma (AHT) in children is often missed in medical encounters, and retinal hemorrhage (RH) is considered strong evidence for AHT. Although head computed tomography (CT) is obtained routinely, all but exceptionally large RHs are undetectable on CT images in children. Objective: To examine whether deep learning-based image analysis can detect RH on pediatric head CT. Design, Setting, and Participants: This diagnostic study included 301 patients diagnosed with AHT who underwent head CT and dilated fundoscopic examinations at a quaternary care children's hospital. The study assessed a deep learning model using axial slices from 218 segmented globes with RH and 384 globes without RH between May 1, 2007, and March 31, 2021. Two additional light gradient boosting machine (GBM) models were assessed: one that used demographic characteristics and common brain findings in AHT and another that combined the deep learning model's risk prediction plus the same demographic characteristics and brain findings. Main Outcomes and Measures: Sensitivity (recall), specificity, precision, accuracy, F1 score, and area under the curve (AUC) for each model predicting the presence or absence of RH in globes were assessed. Globe regions that influenced the deep learning model predictions were visualized in saliency maps. The contributions of demographic and standard CT features were assessed by Shapley additive explanation. Results: The final study population included 301 patients (187 [62.1%] male; median [range] age, 4.6 [0.1-35.8] months). A total of 120 patients (39.9%) had RH on fundoscopic examinations. The deep learning model performed as follows: sensitivity, 79.6%; specificity, 79.2%; positive predictive value (precision), 68.6%; negative predictive value, 87.1%; accuracy, 79.3%; F1 score, 73.7%; and AUC, 0.83 (95% CI, 0.75-0.91). The AUCs were 0.80 (95% CI, 0.69-0.91) for the general light GBM model and 0.86 (95% CI, 0.79-0.93) for the combined light GBM model. Sensitivities of all models were similar, whereas the specificities of the deep learning and combined light GBM models were higher than those of the light GBM model. Conclusions and Relevance: The findings of this diagnostic study indicate that a deep learning-based image analysis of globes on pediatric head CTs can predict the presence of RH. After prospective external validation, a deep learning model incorporated into CT image analysis software could calibrate clinical suspicion for AHT and provide decision support for which patients urgently need fundoscopic examinations.

Topical Anesthetics for Analgesia in Acute Corneal Abrasion: Eye Care Providers Survey.

STUDY OBJECTIVES: To evaluate the current attitudes of ophthalmologists and optometrists regarding topical anesthetic (TA) use in the emergency department (ED) for analgesia in corneal abrasions. METHODS: A survey was distributed through email to ophthalmologists and optometrists, and their responses were deidentified. Three scenarios were presented involving the addition of tetracaine in addition to usual care in the setting of uncomplicated corneal abrasion. A 250-character space for comments and demographic questionnaire followed. A chi-square test, Fisher exact test, or sign test, at a significance level of 0.05, was used. RESULTS: Of the 978 individuals surveyed, 486 responded (MD/DOs: 47.1% and ODs: 52.9%). Topical anesthetic favorability significantly decreased with shorter practice length when the patient was only examined by an ED provider. Topical anesthetic favorability was significantly impacted by respondents' degree type. When respondents were posed with using TAs if the respondents were the patient, the respondents were 22.6% more likely to use TA when compared with their answers in the scenario where the ED provider examined the patient and 20.0% more likely when compared with the scenario where a MD/OD examined the patient. Most did not support tetracaine use. CONCLUSIONS: Although treating pain is associated with improved quality of life, most respondents did not support TA use in the ED. Practice length and degree type significantly impacted responses. Respondents were more inclined to use TAs when the respondents were the patient. Results suggest that eye care providers need additional research data supporting safety before routine use in the ED, given the potential for adverse events with TAs.

Ocular Complications in School-Age Children and Adolescents after Allogeneic Bone Marrow Transplantation.

PURPOSE: To determine the ocular complications in school-age children and adolescents surviving at least 1 year following allogeneic bone marrow transplantation. DESIGN: Retrospective cohort study. METHODS: In this institutional study, 162 patients (7-18 years old) met our inclusion criteria with a mean age of 13.4 years at bone marrow transplantation. Follow-up ranged from 13 months to 12 years (mean 4 years; median 3.2 years). Patient charts were screened for cataract formation, dry eye, and other anterior and posterior segment diseases. RESULTS: Cataract formation was noted in 57 patients. Univariate analysis showed that fractionated total body irradiation, race, and use of cytarabine significantly increased the incidence of cataract formation (P < 0.05). Multivariate analysis of significant variables showed that total body irradiation was a risk factor for cataract formation. Of the 57 patients (97 eyes) who developed cataracts after bone marrow transplantation, 4 patients (6 eyes) required cataract surgery. After surgery, all patients had visual acuities of 20/20 to 20/25. Of the 162 patients, 51 developed dry eyes. Univariate analysis showed that age at transplantation; steroid use, chronic graft-versus-host disease; use of fludarabine, melphalan, and thiotepa; and receiving no pre-transplantation conditioning regimen prior to bone marrow transplant significantly increased the risk of dry eye syndrome (P < 0.05). In multivariate analysis, chronic graft-versus-host disease was a significant risk factor for dry eye syndrome. CONCLUSIONS: Due to the high incidence of cataract formation and dry eye disease in this population, this study proposes these patients be screened using examinations by a pediatric or general ophthalmologist at least every year.

Treatment burden and long-term health deficits of patients with low-grade gliomas or glioneuronal tumors diagnosed during the first year of life.

BACKGROUND: Low-grade gliomas (LGGs) and low-grade glioneuronal tumors (LGGNTs) diagnosed during the first year of life carry unique clinical characteristics and challenges in management. However, data on the treatment burden, outcomes, and morbidities are lacking. METHODS: A retrospective study of LGGs and LGGNTs diagnosed in patients younger than 12 months at St. Jude Children's Research Hospital (1986-2015) was conducted. RESULTS: For the 51 patients (including 31 males), the mean age at diagnosis was 6.47 months (range, 0.17-11.76 months), and the mean follow-up period was 11.8 years (range, 0.21-29.19 years). Tumor locations were hypothalamic/optic pathway (61%), hemispheric (12%), brainstem (12%), cerebellar (8%), and spinal (8%). There were 41 patients with histological diagnoses: 28 had World Health Organization grade 1 tumors, 6 had grade 2 tumors, and 7 had an LGG/LGGNT not definitively graded. Forty-one patients required an active intervention at diagnosis. Throughout their treatment course, 41 patients eventually underwent tumor-directed surgeries (median, 2 surgeries; range, 1-6), 39 received chemotherapy (median, 2 regimens; range, 1-13), and 21 received radiotherapy. Forty patients experienced disease progression (median, 2 progressions; range, 1-18). Ten patients died of progression (n = 5), malignant transformation (n = 2), a second cancer (n = 2), or a shunt infection (n = 1). The 10-year overall survival, progression-free survival, and radiation-free survival rates were 85% ± 5.3%, 16.9% ± 5.3%, and 51.2% ± 7.5%, respectively. Forty-nine patients experienced health deficits (eg, endocrinopathies, obesity, seizures, visual/hearing impairments, neurocognitive impairments, and cerebrovascular disease). Predictors of progression and toxicities were defined. CONCLUSIONS: Infantile LGG/LGGNT is a chronic, progressive disease universally associated with long-term morbidities and requires multidisciplinary intervention.

Neuropsychological outcomes of patients with low-grade glioma diagnosed during the first year of life.

PURPOSE: Low-grade gliomas (LGG) are a heterogeneous group of brain tumors, which are often assumed to have a benign course. Yet, children diagnosed and treated for LGG in infancy are at increased risk for neurodevelopmental disruption. We sought to investigate neuropsychological outcomes of infants diagnosed with LGG. METHODS: Between 1986 and 2013, 51 patients were diagnosed with LGG before 12 months of age and managed at St. Jude Children's Research Hospital. Twenty-five of the 51 patients received a cognitive assessment (68% male; 6.8 ± 3.3 months at diagnosis; 10.5 ± 4.8 years at latest assessment). Approximately half the patients received radiation therapy (n = 12; aged 4.0 ± 3.0 years at radiation therapy), with a median of 2 chemotherapy regimens (range = 0-5) and 1 tumor directed surgery (range = 0-5). RESULTS: The analyses revealed performance below age expectations on measures of IQ, memory, reading, mathematics, and fine motor functioning as well as parent-report of attention, executive, and adaptive functioning. Following correction for multiple comparisons, a greater number of chemotherapy regimens was associated with lower scores on measures of IQ and mathematics. More tumor directed surgeries and presence of visual field loss were associated with poorer dominant hand fine motor control. Radiation therapy exposure was not associated with decline in neuropsychological performance. CONCLUSIONS: Children diagnosed with LGG in infancy experience substantial neuropsychological deficits. Treatment factors, including number of chemotherapy regimens and tumor directed surgeries, may increase risk for neurodevelopmental disruption and need to be considered in treatment planning.

Phase I and pharmacokinetic study of the novel anthracycline derivative 5-imino-13-deoxydoxorubicin (GPX-150) in patients with advanced solid tumors.

PURPOSE: 5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin analog modified in two locations to prevent formation of cardiotoxic metabolites and reactive oxygen species. Preclinical studies have demonstrated anti-cancer activity without cardiotoxicity. A phase I study was performed in order to determine the maximum-tolerated dose (MTD) of GPX-150 in patients with metastatic solid tumors. METHODS: GPX-150 was administered as an intravenous infusion every 21 days for up to 8 cycles. An accelerated dose escalation was used for the first three treatment groups. The dosing groups were (A) 14 mg/m(2), (B) 28 mg/m(2), (C), 56 mg/m(2), (D) 84 mg/m(2), (E) 112 mg/m(2), (F) 150 mg/m(2), (G) 200 mg/m(2), and (H) 265 mg/m(2). Pharmacokinetic samples were drawn during the first 72 h of cycle 1. RESULTS: The MTD was considered to be reached at the highest dosing level of 265 mg/m(2) since dose reduction was required in 5 of 6 patients for neutropenia. The most frequent adverse events were neutropenia, anemia, fatigue, and nausea. No patients experienced cardiotoxicity while on the study. The best overall response was stable disease in four (20 %) patients. Pharmacokinetic analysis revealed an AUC of 8.0 (±2.6) µg · h/mL, a clearance of 607 (±210) mL/min/m(2) and a t1/2ß of 13.8 (±4.6) hours. CONCLUSIONS: GPX-150 administered every 21 days has an acceptable side effect profile and no cardiotoxicity was observed. Further investigation is needed to determine the efficacy of GPX-150 in anthracycline-sensitive malignancies.

Doxorubicin cardiac dysfunction: effects on calcium regulatory proteins, sarcoplasmic reticulum, and triiodothyronine.

Utilizing a model of chronic doxorubicin cardiomyopathy, this study examines the relationship between changes in expression and function of calcium handling proteins and contractile dysfunction. A possible mechanism to account for this relationship is suggested. New Zealand white rabbits were injected with either doxorubicin (1 mg/kg, twice weekly for 8 wk) or 0.9% NaCl. Gene transcript, protein levels, and the function of several proteins from the left ventricle were assessed. Protein levels of sarcoplasmic reticulum (SR) Ca2+ transporting ATPase (SERCA2a and b), Ca2+ release channel (RYR2), calsequestrin, Na/Ca exchanger, mRNA levels of RYR2, and [3H]-ryanodine binding (B(max)) to RYR2 were significantly decreased in doxorubicin-treated rabbits; protein levels of phospholamban, dihydropyridine receptor alpha2 subunit, and SR Ca2+ loading rates were not decreased. However, only protein levels of SERCA2 and RYR2, mRNA levels of RYR2, and Bmax of RYR2 significantly regressed with left-ventricular fractional shortening. Analysis of contractile function of atrial preparations isolated from doxorubicin-treated rabbits revealed that doxorubicin diminished contractility (dF/dt) of rest-potentiated contractions consistent with SR dysfunction. Serum concentrations of free triiodothyronine (T3) decreased in doxorubicin-treated rabbits. Our results suggest that chronic doxorubicin administration in the rabbit causes a SR-dependent contractile dysfunction that may result, in part, from decreased T3.

Species comparison of adenosine A1 receptors in isolated mammalian atrial and ventricular myocardium.

Various species have been used as models to study the effects of adenosine (ADO) on atrial and ventricular myocardium, but few direct tissue comparisons between species have been made. This study further characterizes adenosine A(1) receptor binding, adenylate cyclase activity and direct and indirect A(1) receptor-mediated functional activity in atrial and ventricular tissue from Sprague-Dawley rats and Hartley guinea pigs. Rat right atria (RA) were found to be significantly more sensitive to cyclopentyladenosine (CPA), while guinea pig left atria (LA) were more sensitive to CPA. After the addition of isoproterenol (ISO), the reduction of CPA response in rat RA was significantly greater than in guinea pig; however, after ISO treatment, the guinea pig LA was more sensitive to CPA than the rat. Adenylate cyclase inhibition by CPA was significantly greater in atria and ventricles obtained from guinea pig than rat. In competition binding experiments, guinea pig RA had significantly more high affinity sites than rat, but the K(i)s were not significantly different. There were no significant differences between guinea pig LA and rat LA. Guinea pig ventricular tissue had fewer high affinity sites than rat without any differences in their K(i) values. In antagonist saturation experiments, the density and affinity of A(1) receptors in guinea pig cardiac membranes were significantly greater than in rat. Our results indicate definite species differences as well as tissue differences between rat and guinea pig. These differences must be considered when interpreting studies using rat and guinea pig tissue as models for cardiac function.

Arginine to lysine 108 substitution in recombinant CYP1A2 abolishes methoxyresorufin metabolism in lymphoblastoid cells.

1. Cytochrome P4501A2 (CYP1A2) activates a large number of procarcinogens to carcinogens. Phytochemicals such as flavones can inhibit CYP1A2 activity competitively, and hydroxylated derivatives of flavone (galangin) may be potent, selective inhibitors of CYP1A2 activity relative to CYP1A1 activity. Molecular modelling of the CYP1A2 interaction with hydroxylated derivatives of flavone suggests that a number of hydrophobic residues of the substrate-binding domain engage in hydrogen bonding with such inhibitors. 2. We have tested this model using site-directed mutagenesis of these residues in expression plasmids transfected into the human B-lymphoblastoid cell line, AHH-1 TK+/-. 3. Consistent with the molecular model's predicted placement in the active site, amino acid substitutions at the predicted residues abolished CYP1A2 enzymatic activity. 4. Transfected cell lines contained equal amounts of immunoreactive CYP1A2. 5. Our results support the molecular model's prediction of the critical amino acid residues present in the hydrophobic active site, residues that can hydrogen bond with CYP1A2 inhibitors and modify substrate binding and/or turnover.