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Positive airway pressure therapy is frequently used to treat obstructive sleep apnea in children. However, it is not known whether positive airway pressure therapy results in improvements in the neurobehavioral abnormalities associated with childhood sleep apnea. We hypothesized that positive airway pressure therapy would be associated with improvements in attention, sleepiness, behavior, and quality of life, and that changes would be associated with therapy adherence. Neurobehavioral assessments were performed at baseline and after 3 months of positive airway pressure therapy in a heterogeneous group of 52 children and adolescents. Adherence varied widely (mean use, 170 ± 145 [SD] minutes per night). Positive airway pressure therapy was associated with significant improvements in attention deficits (P < 0.001); sleepiness on the Epworth Sleepiness Scale (P < 0.001); behavior (P < 0.001); and caregiver- (P = 0.005) and child- (P < 0.001) reported quality of life. There was a significant correlation between the decrease in Epworth Sleepiness Scale at 3 months and adherence (r = 0.411; P = 0.006), but not between other behavioral outcomes and adherence. Behavioral factors also improved in the subset of children with developmental delays. These results indicate that, despite suboptimal adherence use, there was significant improvement in neurobehavioral function in children after 3 months of positive airway pressure therapy, even in developmentally delayed children. The implications for improved family, social, and school function are substantial. Clinical trial registered with www.clinicaltrials.gov (NCT 00458406).

Continuous positive airway pressure (CPAP) is effective in treating obstructive sleep apnea in children, but adherence to therapy is low. Our center created an intensive program that aimed to improve adherence. Our objective was to estimate the program's efficacy, cost, revenue and break-even point in a generalizable manner relative to a standard approach. The intensive program included device consignment, behavioral psychology counseling, and follow-up telephone calls. Economic modeling considered the costs, revenue and break-even point. Costs were derived from national salary reports and the Pediatric Health Information System. The 2015 Medicare reimbursement schedule provided revenue estimates. Prior to the intensive CPAP program, only 67.6% of 244 patients initially prescribed CPAP appeared for follow-up visits and only 38.1% had titration polysomnograms. In contrast, 81.4% of 275 patients in the intensive program appeared for follow-up visits (p < .001) and 83.6% had titration polysomnograms (p < .001). Medicare reimbursement levels would be insufficient to cover the estimated costs of the intensive program; break-even points would need to be 1.29-2.08 times higher to cover the costs. An intensive CPAP program leads to substantially higher follow-up and CPAP titration rates, but costs are higher. While affordable at our institution due to the local payer mix and revenue, Medicare reimbursement levels would not cover estimated costs. This study highlights the need for enhanced funding for pediatric CPAP programs, due to the special needs of this population and the long-term health risks of suboptimally treated obstructive sleep apnea.

The goals of these experiments were to efficiently deliver aerosolized adeno-associated virus (AAV) vector to the lungs of Rhesus macaques and to measure gene transfer and expression. To determine optimal lung deposition, we compared four techniques of delivering aerosolized saline admixed with the radioisotope 99mtechnetium (99mTc) nebulized through a mouthpiece (Neb Oral), a laryngeal airway mask (Neb LMA), or an endotracheal tube (Neb ETT), or bronchoscopically delivered by Microsprayer (PennCentury). Total lung deposition fraction, as indicated by gamma scintigraphy, averaged 0.5% (Neb Oral), 1.2% (Neb LMA), 1.8±0.4% (Neb ETT), and 62.3±11.3% (Microsprayer). Because microspraying was the most efficient method of delivery, we used it to administer saline with 99mTc-labeled diethylene-triamine penta-acetic acid (DTPA) admixed with 9×1011 infectious units (i.u.) of AAV serotype 2 (rAAV2) vector encoding green fluorescent protein (GFP; rAAV2-GFP). Initial total and regional lung depositions were quantified by scintigraphy. We analyzed the tissue three weeks later for vector-specific DNA transduction and RNA expression. Radioisotope was detected in all lung regions, reflecting an average dose of 1.33×1010±9.5×109 i.u. per region. Regional data indicated an increase in expression when the dose exceeded 3×109 i.u. (P=0.030). We conclude that expression of rAAV2-GFP in lungs appears to be related to depositing a regional threshold dose greater than 3×109 i.u., easily achieved by bronchoscopic microspraying.

Bronchoscopic microspraying of recombinant adeno-associated viral (rAAV) vectors targets high doses of vector directly to pulmonary epithelium. Single-dose endobronchial gene therapy trials have been accomplished in cystic fibrosis patients; however, repeated dosing strategies are likely essential for lifetime correction. These studies address whether serial redosing with rAAV2 vectors results in an antiserotypic response and, furthermore, whether it triggers an inflammatory response prohibitive to transgene expression. Serial redosing of 9 × 1011 infectious units of aerosolized rAAV2 vectors to rhesus macaques resulted in successful gene transfer by quantitative PCR (1.43 × 109 copies/g tissue) and transgene expression. Additionally, confocal microscopy and immunohistochemical analysis demonstrated in situ expression localized to the pulmonary epithelium. Although serial redosing did induce a heightened anti-neutralizing antibody response in sera, gene transfer prevailed with resultant expression. This study is the first to demonstrate successful gene transfer subsequent to repeated aerosolized doses of rAAV2 in immunocompetent nonhuman primates without associated inflammatory responses prohibitive to transgene expression.

Introduction Individuals with Down syndrome (DS) are at increased risk for obstructive sleep apnea syndrome (OSAS), which may not completely resolve after adenotonsillectomy. This has led to an increase in referral for treatment with positive airway pressure (PAP). Treatment with PAP in this group may be challenging. The purpose of this study is to describe the experience of youth with DS and OSAS (DS-OSAS) referred for PAP at a tertiary pediatric sleep center. Methods Retrospective study of youth with DS-OSAS prescribed PAP between 01/01/14 and 12/31/16. Inclusion criteria: youth with DS-OSAS treated with continuous-(CPAP), bi-level-(BLPAP) or auto-PAP and followed for at least two years after initiation by an interdisciplinary team (physicians, psychologists, nurse practitioner, nurses, and respiratory therapists). Demographic and clinical characteristics were examined. Adherence to PAP at 0-6, 6-12, 12-18, and 18-24 month intervals after initiation was analyzed. Data are presented as mean±SD, median[IQR] or percent. Friedman repeated measures analysis of variance on ranks were performed. Results 441 children were initiated on PAP. Of these, 61 had DS-OSAS (8.9±5.5 years; 53% females; 56% White), 72% received CPAP and 16.3%, BLPAP. Most completed a titration study (77%). 36% were discharged from the program (transitioned to adult care, moved or resolved); 7% sought alternative treatments; 15% did not tolerate PAP or were lost to follow up. PAP adherence expressed as percentage of nights used and minutes used on nights used was 42.1[17.1-78.6]% and 126[31.8-358.5]mins at 0-6 (N=50); 63.6[14.3-92.4]% and 237[77.0-438.5]mins at 6-12 (N=37); 64.0[7.7-96.4]% and 268.5[83.8-423.2]mins at 12-18 (N=32); and 66[29.0-97.4]% and 219.0[62.0-474.5]mins at 18-24 months (N=26). Of those with adherence data at each interval (N=21), the median minutes used was 184 mins at 0-6, 290 mins at 6-12, 321 mins at 12-18, and 219 mins at 18-24 months (p=0.008). Conclusion Most children with DS-OSAS tolerated titration polysomnogram and treatment with PAP. A third of patients could be safely discharged. Few children were lost to follow up. Of those with complete data, adherence improved over time. Support (If Any) None

Introduction In-laboratory titration polysomnography (PSG) is standard to determine optimal therapeutic continuous positive airway pressure (CPAP) in children with obstructive sleep apnea syndrome (OSAS) treated with CPAP. Use of auto titrating CPAP devices (autoCPAP) as an alternative is not well studied in children. We hypothesized that autoCPAP-derived pressures (PAUTO) correlate with the gold standard of titration PSG pressure (PPSG). Methods Retrospective study of children cared for in a pediatric sleep center initiated on autoCPAP between 2007 and 2017 who had a titration PSG. Children who used autoCPAP ≥ 120 minutes on the nights used within 90 days of titration PSG and whose residual obstructive apnea hypopnea index (OAHI) decreased by ≥ 75% were included in the analysis. PAUTO were obtained from usage downloads and compared to PPSG. PPSG predictive factors were analyzed by median regression. Non-parametric methods were used for analysis. Results 110 children were initiated on autoCPAP and 44 satisfied inclusion criteria. Age (mean±SD) was 12.9±4.0 years, 63.6% were obese (BMI ≥ 95%). PPSG median[IQR] was 8[7-11] cmH2O, PAUTO mean pressure (PMEAN) 6.2[5.6-7.6] cmH2O, peak mean pressure (PPEAKMEAN) 9.4[7.7-11.1] cmH2O, and average device pressure < 90% of the time (P90) 8.1[7.2-9.7] cmH2O. All three PAUTO correlated with PPSG (rho 0.34, 0.36, 0.33, respectively; p <0.05). PMEAN was significantly lower than the other three pressures (p<0.0002). Median regression analysis demonstrated that after adjusting for patient characteristics such as age, BMI, obesity status, baseline OAHI, race and gender, PAUTO remained significant predictors of PPSG (p<0.05). There were no significant interactions between these patient characteristics and PAUTO. Conclusion AutoCPAP can be effectively used in children. PPEAKMEAN and P90 are in better agreement with PPSG. PMEAN was lower than PPSG underscoring that autoCPAP decreases pressure when less pressure is needed. Long-term studies of autoCPAP for the treatment of OSAS in children are needed to determine its impact on adherence and health outcomes in children. Support (If Any) T32HL07713, K01HL130719

Background: Studies have identified associations between intimate partner violence (IPV) and elevated risk of sexually transmitted infections (STI). An estimated 6% of women in the United States have experienced physical and/or sexual assault inflicted by an intimate partner in the previous year. Of those with an STI, chlamydia is disproportionately reported for women. In 2009, New York State legalized Expedited Partner Therapy (EPT) for chlamydial infections; however clinicians are lacking guidance with respect to appropriate use of EPT when IPV is a concern. Objectives: To detect associations between IPV and female opinions regarding EPT. Methods: Study participants were women receiving health services at an urban Upstate NYS health center who completed a self-administered questionnaire. Exposure to IPV within the past year was measured by the composite abuse scale (CAS). Recent IPV was defined by a CAS score >3 and all others were defined as no recent IPV exposure. Results: Among 260 respondents, 130 (50%) reported recent IPV. Compared to women with no recent IPV, those recently exposed were more likely to report >1 current sex partner (p<0.001), more likely to agree they had at least one partner they would not trust to give them a prescription to treat an STI [adjusted prevalence ratio (aPR) = 2.8, 95% Confidence Interval (CI) = (1.7, 4.6)] and less likely to agree that it is okay for a doctor to give an STI-infected patient a written prescription with the name of his or her sexual partner (aPR = 0.7, 95% CI = 0.5-0.9). Conclusions: Differences in the acceptability of EPT exist between women recently and not recently exposed to IPV. These findings suggest that women experiencing IPV are less likely to view EPT as beneficial. Partner management strategies should be developed in the context of IPV risk assessment, and guidance should be provided to clinicians in this regard as EPT is implemented and at a minimum, prescriptions with a specific notation of \"EPT\" in lieu of a person's name should be distributed for EPT.

Little is known about how the large brains of mammals are accommodated into the dazzling diversity of their skulls. It has been suggested that brain shape is influenced by relative brain size, that it evolves or develops according to extrinsic or intrinsic mechanical constraints, and that its shape can provide insights into its proportions and function. Here, we characterize the shape variation among 84 marsupial cranial endocasts of 57 species including fossils, using three-dimensional geometric morphometrics and virtual dissections. Statistical shape analysis revealed four main patterns: over half of endocast shape variation ranges from elongate and straight to globular and inclined; little allometric variation with respect to centroid size, and none for relative volume; no association between locomotion and endocast shape; limited association between endocast shape and previously published histological cortex volumes. Fossil species tend to have smaller cerebral hemispheres. We find divergent endocast shapes in closely related species and within species, and diverse morphologies superimposed over the main variation. An evolutionarily and individually malleable brain with a fundamental tendency to arrange into a spectrum of elongate-to-globular shapes—possibly mostly independent of brain function—may explain the accommodation of brains within the enormous diversity of mammalian skull form.