Stressful life events, caregiver depressive symptoms, and child asthma symptom-free days: a longitudinal analysis.

OBJECTIVE: To examine relationships among stressful life events (SLE), caregiver depression, and asthma symptom free days (SFDs) in publicly insured Black children aged 4-12 years with persistent asthma. METHODS: Secondary analysis of longitudinal data from a clinical trial assessing the efficacy of a six-month parental stress management intervention. Using repeated measures Poisson regression, we constructed four models of SLE (Rochester Youth Development Stressful Life Events scale-Parent Items), caregiver depression (Center for Epidemiologic Studies Depression scale ≥ 11), and child asthma symptom-free days (SFDs) in the prior 14 days. RESULTS: There was no association between SLE and child SFDs, but there was for caregiver depression (Incidence Rate Ratio [IRR]: 0.904; 95% CI 0.86-0.95). The interaction between SLE and caregiver depression was not significant. A specific SLE (recent serious family accident or illness) predicted fewer child SFDs (IRR: 0.91, 95% CI: 0.85-0.98). In the interaction model between caregiver depression and recent accident/illness, caregiver depression was associated with fewer child SFDs (IRR: 0.95, 95% CI: 0.91-0.99) as was the interaction between caregiver depression and recent accident/illness (IRR: 0.77, 95% CI 0.66-0.91); but the relationship between recent accident/illness and child SFDs was not (IRR: 1.00, 95% CI, 0.92-1.09), meaning accident/illness was only associated with fewer child SFDs among depressed caregivers. CONCLUSIONS: In a sample of publicly insured Black children with persistent asthma, caregiver depression was negatively associated with child SFDs while overall SLE were not. A recent family accident or illness was negatively associated with child SFDs only when the caregiver was depressed.

Major Adverse Dystrophinopathy Events (MADE) Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy.

Background: Overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden-the Major Adverse Dystrophinopathy Event (MADE) Score. We hypothesized that a higher MADE score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation. Methods: Duchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and longitudinally.Associations between MADE score and mortality were examined. Results: Duchenne Natural History Study enrolled 440 males, 12.6 ±6.1 years old, with 3,559 visits over 4.6 ±2.8 years, 45 deaths. MADE score increased with age and nonambulatory status. Mean MADE score per visit was 19 ±10 for those who died vs. 9.8 ±9.3 in survivors p=0.03. Baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). Rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001. Conclusion: A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE score predicted Duchenne Natural History Study mortality. MADE score can be used for serial heart failure assessment in males and may serve as an endpoint for Duchenne muscular dystrophy clinical research.

Cardiac and pulmonary findings in dysferlinopathy: A 3-year, longitudinal study.

INTRODUCTION/AIMS: There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype. METHODS: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11-86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo). RESULTS: Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population. DISCUSSION: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.

Longitudinal motor function in proximal versus distal DMD pathogenic variants.

INTRODUCTION/AIMS: There is considerable heterogenicity in clinical outcomes in Duchenne muscular dystrophy (DMD). The aim of this study was to assess whether dystrophin gene (DMD) pathogenic variant location influences upper or lower extremity motor function outcomes in a large prospective cohort. METHODS: We used longitudinal timed and quantitative motor function measurements obtained from 154 boys with DMD over a 10-y period by the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS) to understand how the trajectories of motor function differ based on proximal versus distal DMD pathogenic variants. Proximal variants were defined as located proximal to 5' DMD intron 44, and distal variants as those including nucleotides 3' DMD including intron 44. Distal DMD variants are predicted to alter the expression of short dystrophin isoforms (Dp140, Dp116, and Dp71). We compared various upper extremity and lower extremity motor function measures in these two groups, after adjusting for total lifetime corticosteroid use. RESULTS: The time to loss-of-ambulation and timed motor function measurements of both upper and lower limbs over a 10-y period were comparable between boys with proximal (n = 53) and distal (n = 101) DMD pathogenic variants. Age had a significant effect on several motor function outcomes. Boys younger than 7 y of age (n = 49) showed gain in function whereas boys 7 y and older (n = 71) declined, regardless of dystrophin pathogenic variant location. DISCUSSION: The longitudinal decline in upper and lower motor function is independent of proximal versus distal location of DMD pathogenic variants.

Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.

BACKGROUND: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. METHODS AND FINDINGS: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators. CONCLUSIONS: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy. TRIAL REGISTRATION: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].

The CINRG Becker Natural History Study: Baseline characteristics.

We performed an observational, natural history study of males with in-frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). A prospective natural history study collected longitudinal medical, strength, and timed function assessments. Eighty-three participants with genetically confirmed BMD were enrolled (age range 5.6-75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in-frame deletions that corresponded to an out-of-frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. A prospective natural history cohort with in-frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy.

Troponin I Levels Correlate with Cardiac MR LGE and Native T1 Values in Duchenne Muscular Dystrophy Cardiomyopathy and Identify Early Disease Progression.

Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Elevated troponin levels are observed in DMD and may vary with disease progression. We studied troponin levels in DMD related to cardiac fibrosis and native T1 measures. This is a prospective, cross-sectional, observational study of 30 DMD subjects measuring native T1 levels and late gadolinium enhancement (LGE) on cardiac MR imaging (CMR) correlated with temporally associated serum troponin I levels. Non-parametric analyses including Spearman correlations and Kruskal-Wallis test were performed between groups. p values resulting from the pair-wise comparisons were adjusted for multiple comparisons using the Sidak method where appropriate. There were 15 DMD subjects with no LGE (age 12 ± 3 yo; EF% 60 ± 5) and troponin I level of 0.05 ± 0.08 ng/ml, of which three had an abnormal troponin level (over 0.04 ng/ml); 7 DMD subjects with mild LGE (age 17 ± 5 yo, EF% 52 ± 8) and troponin I level of 0.28 ± 0.36 ng/ml, of which five had an abnormal troponin level; and 8 DMD subjects with moderate-to-severe LGE (age 16 ± 6 yo; EF% 54 ± 8) and troponin I level of 0.11 ± 0.14 ng/ml, of which four had an abnormal troponin level. Troponin I levels in DMD subjects with mild LGE was significantly increased compared to subjects with no LGE (p = 0.02). There was a statistically significant positive correlation between troponin I levels and MOLLI septal native T1 values (r2 = 0.173, p = 0.02). Overall, MOLLI lateral native T1 levels were increased with moderate-severe LGE compared to mild and none (p < 0.01). Serum biomarker troponin I levels were increased in DMD subjects with mild LGE and correlated with MOLLI septal native T1 values. Troponin I levels may be a useful minimally invasive outcome marker to monitor myocardial disease progression in DMD cardiomyopathy.

Optimizing Perioperative Red Blood Cell Utilization and Wastage in Pediatric Craniofacial Surgery.

Utilization, wastage, and adverse consequences of assigning one full red blood cell (RBC) unit were investigated for children undergoing craniosynostosis surgery. The authors hypothesized that significant RBC wastage in the perioperative period exists for pediatric craniofacial surgery. The authors sought to determine what factors could guide patient-specific blood product preparation by evaluating utilization and wastage of RBCs in pediatric patients undergoing surgical correction of craniosynostosis. Eighty-five children with craniosynostosis undergoing surgical correction at our institution between July 2013 and June 2015 were identified. Fifty-three patients received RBC transfusion in the perioperative period, while 32 patients were not transfused. Primary outcome measures were intraoperative, postoperative, and total percent of RBC wastage. Secondary analysis compared the impact of patient weight and procedure type on perioperative RBC wastage. Of the 53 patients who received perioperative RBC transfusion, 35 patients received a volume of blood less than the full volume of the RBC unit while 18 patients received the full volume of blood. There was no significant relationship between perioperative RBC wastage, the type of craniofacial procedure performed, or the duration of surgical time. Children who received a perioperative transfusion and had RBC wastage weighed significantly less than those who received a full volume. These findings suggest that for craniofacial surgical patients weighing less than 10 kg, a protocol that splits cross-matched RBC units can decrease perioperative RBC wastage and blood donor exposure. A future prospective study will determine the success of this intervention as well as the potential to decrease exposure to multiple blood donors.

Association Study of Exon Variants in the NF-κB and TGFß Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy.

The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor ß [TGFß]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 × 10-6). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFß pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 10-5). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.

Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study.

BACKGROUND: Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. METHODS: For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. FINDINGS: 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501). INTERPRETATION: In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death. FUNDING: US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

Perioperative Outcomes and Surgical Case Volume in Pediatric Complex Cranial Vault Reconstruction: A Multicenter Observational Study From the Pediatric Craniofacial Collaborative Group.

BACKGROUND: Complex cranial vault reconstruction (CCVR) performed to treat craniosynostosis can be associated with significant blood loss, transfusion, and perioperative complications. The aim of this study was to examine the effect of CCVR surgical case volume on perioperative outcomes. We hypothesized that surgical case volume is not associated with differences in perioperative outcomes. The study primary outcome was total perioperative blood donor exposures. Secondary outcomes included the total perioperative transfusion volume, major complications, and intensive care unit and hospital length of stay. METHODS: The multicenter Pediatric Surgery Perioperative Registry was queried for infants and children undergoing CCVR between June 2012 and September 2016. Institutions were categorized into low, middle, or high surgical case volume groups based on tertiles of the average number of cases performed per month. Primary and secondary outcomes were analyzed with respect to these groupings. RESULTS: The query yielded 1814 CCVR cases from 33 institutions. Demographics were similar among the 3 study groups. An inverse relationship between surgical case volume and total perioperative blood donor exposures was observed (P < .001). The low-volume group had higher perioperative transfusion volumes (P = .02 versus middle; P = .01 versus high). There was no significant relationship between surgical case volume and the incidence of major postoperative complications or hospital length of stay. CONCLUSIONS: In this study, low surgical case volumes were associated with increased total blood donor exposures and increased perioperative transfusion volumes. Hospital length of stay was homogeneous in the 3 groups, suggesting a limited overall clinical impact of the observed transfusion outcome differences.

Association between perioperative surgical home implementation and transfusion patterns in adolescents with idiopathic scoliosis undergoing spinal fusion.

BACKGROUND: Blood transfusions in patients with adolescent idiopathic scoliosis after fusion have been associated with increased morbidity, mortality, and cost. OBJECTIVE: The aim of this study was to evaluate the association between implementation of blood-conservation strategies within the perioperative surgical home on transfusion rates for patients with adolescent idiopathic scoliosis undergoing spinal fusion. METHODS: Two hundred and thirteen patients (44 preperioperative surgical home, 169 postperioperative surgical home) who underwent posterior spine fusion for adolescent idiopathic scoliosis between 23 June 2014, and 30 July 2017, were enrolled in this case control study. The perioperative surgical home implemented in March 2015 involved evidence-based perioperative interventions to create a standardized clinical pathway including judicious use of crystalloid management, restrictive transfusion strategy, routine use of cell saver, and standardized administration of anti-fibrinolytics. The primary outcome was odds of perioperative transfusion. Secondary outcomes included volumes of crystalloid, albumin, cell saver, packed red blood cells as well as calculated blood loss. Other variables that were documented included antibrinolytic total dose, mean arterial pressure, temperature, laboratory values, intrathecal morphine dosing, and surgical time. Statistical methods included t test and logistic regression. RESULTS: For the postperioperative surgical home, the odds of perioperative transfusion were 0.30 (95% CI 0.13-0.70), as compared to preperioperative surgical home. In terms of secondary outcomes, calculated blood loss was significantly lower in the postperioperative surgical home patients (27.0 mL/kg preperioperative surgical home vs 22.8 mL/kg postperioperative surgical home; mean difference = -0.24 [-0.44, -0.04]). Although no difference was noted in the amount of intraoperative cell saver or albumin administered, a reduction was noted in mean intraoperative crystalloid given postperioperative surgical home (41.4 mL/kg ± 20.4 mL/kg preperioperative surgical home vs 28.0 mL/kg ± 13.7 mL/kg postperioperative surgical home; log mean difference = 0.37 [95% CI 0.21-0.53], P < 0.001). Postperioperative surgical home patients also had a significantly higher temperature nadir (mean difference = -0.47 [95% CI -0.70 to -0.23]; P < 0.001), received a significantly higher total anti-fibrinolytic dose (mean difference = -3939 [95% CI -5364 to -2495]; P < 0.001), and were exposed to shorter surgical times (mean difference = 0.72 [95% CI 0.36-1.09]; P < 0.001). CONCLUSIONS: Implementation of blood-conservation strategies as part of a perioperative surgical home for patients with adolescent idiopathic scoliosis undergoing posterior spine fusion resulted in significant decrease in perioperative blood transfusions.

Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy.

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster.

Intraoperative Management by a Craniofacial Team Anesthesiologist is Associated With Improved Outcomes for Children Undergoing Major Craniofacial Reconstructive Surgery.

The benefits of using a dedicated team for complex surgeries are well established for certain specialties, but largely unknown for others. The aim of this study was to determine whether management by a dedicated craniofacial team anesthesiologist would impact perioperative outcomes for children undergoing major surgery for craniosynostosis. Sixty-two children undergoing complex cranial vault reconstruction were identified. Fifty-four patients were managed by the craniofacial anesthesia team, while 8 patients were not. Primary outcome measures were calculated blood loss, red blood cell transfusion volume, blood donor exposures, extubation rate, and postoperative complication rate. Secondary outcome measures included intraoperative opioid administration, crystalloid and colloid administration, intraoperative complication rate, and intensive care unit (ICU) and hospital length of stay. Children cared for by the craniofacial team had significantly lower calculated blood loss, reduced red blood cell transfusion volume, fewer blood donor exposures, less crystalloid administration, higher rate of postoperative extubation, fewer postoperative complications, and decreased ICU and hospital length of stay than patients who were managed by noncraniofacial team anesthesiologists. There were no significant differences in demographics, opioid administration, colloid volume administration, or intraoperative complication rates between the 2 groups. Management by a craniofacial team anesthesiologist was associated with improved outcomes in children undergoing major craniofacial reconstructive surgery. While some variability can be attributed to provider-volume relationship, these findings suggest that children may benefit from a subspecialty anesthesia team-based approach for the management of craniofacial surgery, and potentially other similar high-risk cases.

Characterization of mucoid and serous middle ear effusions from patients with chronic otitis media: implication of different biological mechanisms?

BACKGROUND: Chronic otitis media with effusion (COME) is characterized by persistent middle ear effusions that are in most cases highly viscous, but some patients present with serous fluid. This study aimed at comprehensively characterizing the macromolecular composition of mucoid vs. serous middle ear effusions (MEEs). METHODS: MEEs from patients with COME were analyzed for proteins by mass spectrometry (MS) and western blot techniques, total DNA quantity, bacterial DNA (16S sequencing), and cytokine content. Proteomics datasets were studied in Ingenuity Pathway Analysis (IPA). RESULTS: Mucoid samples showed a global tendency of increased pro-inflammatory mediators. Interleukin-1ß (IL-1ß) and IL-10 were significantly more abundant in serous samples (p < 0.01). Mucoid samples had higher DNA quantity (p = 0.04), more likely to be positive in MUC5B protein (p = 0.008) and higher peptide counts (12,786 vs. 2225), as well as an overall larger number of identified proteins (331 vs. 177), compared to serous. IPA found the mucoid sample dataset to be related to immune cell function and epithelial remodeling, whereas the serous sample dataset showed acute responses and blood-related proteins. Interestingly, serous samples showed more bacterial DNA than mucoid ones, with less bacterial genera variability. CONCLUSION: This study demonstrates divergent immune responses in children with COME by effusion quality.

Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.

Myocardial Strain Using Cardiac MR Feature Tracking and Speckle Tracking Echocardiography in Duchenne Muscular Dystrophy Patients.

Duchenne muscular dystrophy (DMD) is an inherited X-linked disorder with an incidence of 1 in 3500 male births, and cardiomyopathy is becoming the leading cause of death. While Cardiac MRI (CMR) and late gadolinium enhancement (LGE) are important tools in recognizing myocardial involvement, myocardial strain imaging may demonstrate early changes and allow patients to avoid gadolinium contrast. We performed CMR feature tracking (FT) and echo-based speckle tracking (STE) strain measures on DMD patients and age/sex matched controls who had received a CMR with contrast and transthoracic echocardiogram. Data were collected for longitudinal strain in the apical four-chamber view and circumferential strain in the mid-papillary parasternal short axis. Segmental wall analysis was performed and compared with the presence of LGE. Data were analyzed using student's t tests or one-way ANOVA adjusting for multiple comparisons. We measured 24 subjects with DMD and 8 controls. Thirteen of 24 DMD subjects were LGE positive only in the lateral segments in short-axis views. Average circumferential strain (CS) measured by FT was significantly decreased in DMD compared to controls (- 18.8 ± 6.1 vs. - 25.5 ± 3.2; p < 0.001) and showed significant differences in the anterolateral, inferolateral, and inferior segments. Average CS by STE trended towards significance (p = 0.06) but showed significance in only the inferior segment. FT showed significant differences in the inferolateral segment between LGE positive (- 15.5 ± 9.0) and LGE negative (- 18.2 ± 8.3) in DMD subjects compared to controls (- 28.6 ± 7.3; p ≤ 0.04). FT also showed significant differences between anteroseptal and inferolateral segments within LGE-positive (p < 0.003) and LGE-negative (p < 0.03) DMD subjects while STE did not. There were no significant differences in longitudinal strain measures. CMR-FT-derived myocardial strain was able to demonstrate differences between subjects with DMD and controls not detected by STE. FT was also able to demonstrate differences in LGE-positive and LGE-negative segments within patients with DMD. FT may be able to predict LGE-positive segments in DMD without the use of gadolinium contrast.

Neonatal detection of Aicardi Goutières Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots.

BACKGROUND: Aicardi Goutières Syndrome (AGS) is a heritable interferonopathy associated with systemic autoinflammation causing interferon (IFN) elevation, central nervous system calcifications, leukodystrophy and severe neurologic sequelae. An infant with TREX1 mutations was recently found to have abnormal C26:0 lysophosphatidylcholine (C26:0 Lyso-PC) in a newborn screening platform for X-linked adrenoleukodystrophy, prompting analysis of this analyte in retrospectively collected samples from individuals affected by AGS. METHODS: In this study, we explored C26:0 Lyso-PC levels and IFN signatures in newborn blood spots and post-natal blood samples in 19 children with a molecular and clinical diagnosis of AGS and in the blood spots of 22 healthy newborns. We used Nanostring nCounter™ for IFN-induced gene analysis and a high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS) newborn screening platform for C26:0 Lyso-PC analysis. RESULTS: Newborn screening cards from patients across six AGS associated genes were collected, with a median disease presentation of 2months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>0.4µM), that would have resulted in a second screen being performed in a two tier screening system for X-linked adrenoleukodystrophy (X-ALD). The median (95%CI) of first tier C26:0 Lyso-PC values in AGS individuals (0.43µM [0.37-0.48]) was higher than that seen in controls (0.21µM [0.21-0.21]), but lower than X-ALD individuals (0.72µM [0.59-0.84])(p<0.001). Fourteen of 19 children had elevated expression of IFN signaling on blood cards relative to controls (Sensitivity 73.7%, 95%CI 51-88%, Specificity 95%, 95% CI 78-99%) including an individual with delayed disease presentation (36months of age). All five AGS patients with negative IFN signature at birth had RNASEH2B mutations. Consistency of agreement between IFN signature in neonatal and post-natal samples was high (0.85). CONCLUSION: This suggests that inflammatory markers in AGS can be identified in the newborn period, before symptom onset. Additionally, since C26:0 Lyso-PC screening is currently used in X-ALD newborn screening panels, clinicians should be alert to the fact that AGS infants may present as false positives during X-ALD screening.

Interleukin 1 Receptor-Like 1 Protein (ST2) is a Potential Biomarker for Cardiomyopathy in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare, fatal X-linked disorder characterized by the lack of dystrophin, a key sarcolemma muscle protein. Cardiac failure is a significant cause of death in DMD subjects. The purpose of our research was to identify potential cardiac serum biomarkers associated with DMD cardiomyopathy. This is an observational, case-controlled study using subjects from the CINRG DMD natural history study with cardiomyopathy (ejection fraction (EF) <55%; shortening fraction (SF) <28%), subjects without cardiomyopathy (EF ≥ 55%; SF ≥ 28%) compared to normal healthy volunteer subjects. The DMD with cardiomyopathy group had significantly lower average EF and SF (EF = 45 ± 10/SF = 25 ± 2%) than the DMD without cardiomyopathy group (EF = 58 ± 5% and SF = 32 ± 3%; p < 0.01). Among a selected set of potential biomarkers for cardiomyopathy (MMP9, BNP, GAL3, CRP, LEP, TNC, TLR4 and ST2) we validated ST2 as significantly elevated in the serum of DMD cardiomyopathy group (35,798 ± 4884 pg/mL) compared to normal controls (9940 ± 2680 pg/mL; p < 0.01; n = 6). Matrix metallopeptidase 9 (MMP9) levels were found significantly increased in both DMD groups compared to controls (p < 0.01). No significant differences were seen in BNP, GAL3, CRP, LEP, TNC or TLR4 levels. Increased ST2 levels were found in serum of DMD subjects compared to healthy volunteers and further elevated in DMD subjects with cardiomyopathy. Future studies correlating cardiomyopathy with ST2 levels may allow for improved non-invasive monitoring of cardiac disease in DMD subjects.

The financial impact of clinic no-show rates in an academic pediatric otolaryngology practice.

PURPOSE: To investigate determinants of no-show rates in an academic pediatric otolaryngology practice including appointment time, age, sex, new patient status, payer mix, and median household income by zip code. MATERIALS AND METHODS: Retrospective chart review of clinic no-show rates and patient demographics in a free standing children's hospital and affiliated outpatient clinics across eight providers in a one-year period. RESULTS: Analysis shows that the overall no-show rate across all providers was 15% with the highest rate of 19% in the zip code with the lowest median income. Highest no-shows are in June, but overall, seasons did not play a significant role in no-show rates. Male gender, morning appointments, and having public insurance appear to significantly predict no-shows. Lost revenue on no-shows range from $191K to $384K per year. The average percentage of the amount billed paid by insurance range from the lowest by out-of-state Medicaid at 16% to the highest by managed care at 54%. CONCLUSIONS: No-show rates account for a significant portion of lost revenue in the outpatient setting for an academic practice, and can be predicted by lower median income, male gender, morning appointments, and public insurance. Such patients may need different appointment reminders. Future clinic templates should be optimized for no-shows to increase productivity and access to care.