Nemours Children’s Clinic

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

BACKGROUND: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS: Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02). CONCLUSIONS: Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).

BACKGROUND: Previous reports have indicated high complication rates associated with non-fusion surgery in patients with early-onset scoliosis. This study was performed to evaluate the clinical and radiographic complications associated with growing-rod treatment. METHODS: Data from the multicenter Growing Spine Study Group database were evaluated. Inclusion criteria were growing-rod treatment for early-onset scoliosis and a minimum of two years of follow-up. Patients were divided into treatment groups according to rod type (single or dual) and rod location (subcutaneous or submuscular). Complications were categorized as wound, implant, alignment, and general (surgical or medical). Surgical procedures were classified as planned and unplanned. RESULTS: Between 1987 and 2005, 140 patients met the inclusion criteria and underwent a total of 897 growing-rod procedures. The mean age at the initial surgery was six years, and the mean duration of follow-up was five years. Eighty-one (58%) of the 140 patients had a minimum of one complication. Nineteen (27%) of the seventy-one patients with a single rod had unplanned procedures because of implant complications, compared with seven (10%) of the sixty-nine patients with dual rods (p ≤ 0.05). Thirteen (26%) of the fifty-one patients with subcutaneous rod placement had wound complications compared with nine of the eighty-eight patients (10%) with submuscular rod placement (p ≤ 0.05). The patients with subcutaneous dual rods had more wound complications, more prominent implants, and more unplanned surgical procedures than did those with submuscular dual rods (p ≤ 0.05). The risk of complications occurring during the treatment period decreased by 13% for each year of increased patient age at the initiation of treatment. The complication risk increased by 24% for each additional surgical procedure performed. CONCLUSIONS: Regardless of treatment modality, the management of early-onset scoliosis is prolonged; therefore, complications are frequent and should be expected. Complications can be reduced by delaying initial implantation of the growing rods if possible, using dual rods, and limiting the number of lengthening procedures. Submuscular placement reduces wound and implant-prominence complications and reduces the number of unplanned operations.

BACKGROUND: The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS: We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS: We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS: Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).

Prednisone treatment causes protein wasting and adds additional risks to a patient, whereas human growth hormone (hGH) treatment causes positive nitrogen balance. To determine whether concomitant administration of hGH prevents the protein catabolic effects of prednisone, four groups of eight healthy volunteers each were studied using isotope dilution and nitrogen balance techniques after 7 d of placebo, hGH alone (0.1 mg.kg-1.d-1), prednisone alone (0.8 mg.kg-1.d-1), or prednisone plus hGH (n = 8 in each group). Whether protein balance was calculated from the leucine kinetic data or nitrogen balance values, prednisone alone induced protein wasting (P less than 0.001), whereas hGH alone resulted in positive (P less than 0.001) protein balance, when compared to the placebo-treated subjects. When hGH was added to prednisone therapy, the glucocorticoid-induced protein catabolism was prevented. Using leucine kinetic data, negative protein balance during prednisone was due to increased (P less than 0.05) proteolysis, whereas hGH had no effect on proteolysis and increased (P less than 0.01) whole body protein synthesis. During combined treatment, estimates of proteolysis and protein synthesis were similar to those observed in the placebo treated control group. In conclusion, human growth hormone may have a distinct role in preventing the protein losses associated with the administration of pharmacologic doses of glucocorticosteroids in humans.

Quantitative mixed models were used to examine literature published from 1966 through 2016 on the effectiveness of Direct Instruction. Analyses were based on 328 studies involving 413 study designs and almost 4,000 effects. Results are reported for the total set and subareas regarding reading, math, language, spelling, and multiple or other academic subjects; ability measures; affective outcomes; teacher and parent views; and single-subject designs. All of the estimated effects were positive and all were statistically significant except results from metaregressions involving affective outcomes. Characteristics of the publications, methodology, and sample were not systematically related to effect estimates. Effects showed little decline during maintenance, and effects for academic subjects were greater when students had more exposure to the programs. Estimated effects were educationally significant, moderate to large when using the traditional psychological benchmarks, and similar in magnitude to effect sizes that reflect performance gaps between more and less advantaged students.

BACKGROUND AND PURPOSE: Assessing disability is important, and numerous interviewer-assisted and self-report questionnaires are used to accomplish this task. These questionnaires can be classified as being generic, condition or disease specific, or patient specific. The purpose of this study was to determine test-retest reliability, construct validity, and sensitivity to change of the Patient-Specific Functional Scale (PSFS) when applied to patients with knee dysfunction. SUBJECTS: Subjects were 38 physician-referred patients with knee dysfunction. METHODS: The PSFS and the Medical Outcomes Study 36-Item Short-Form Health Survey were administered at a patient's initial visit and following 2 to 3 weeks of treatment. An assessment of global change was also made by the patient and clinician at follow-up. These measures allowed the assessment of construct validity and sensitivity to change. To obtain an estimate of reliability, the PSFS was also administered within 72 hours of the initial assessment. RESULTS: Test-retest reliability and sensitivity to change were excellent (intraclass correlation coefficient [type 2,1] R = .84 and Pearson's r = .78, respectively). Validity was also confirmed. CONCLUSION AND DISCUSSION: Previous investigation on persons with low back pain suggested that the PSFS has promising measurement properties. The results of this study provide further evidence supporting the reliability, validity, and efficiency of the PSFS. Further investigation is needed to determine the extent to which the PSFS can be applied across a variety of conditions and age groups.

OBJECTIVE: The purpose of this study was to determine the clinical benefits of intense-pulsed-light therapy for the treatment of dry-eye disease caused by meibomian gland dysfunction (MGD). BACKGROUND DATA: MGD is the leading cause of evaporative dry eye disease. It is currently treated with a range of methods that have been shown to be only somewhat effective, leading to the need for advanced treatment options. METHODS: A retrospective noncomparative interventional case series was conducted with 91 patients presenting with severe dry eye syndrome. Treatment included intense-pulsed-light therapy and gland expression at a single outpatient clinic over a 30-month study. Pre/post tear breakup time data were available for a subset of 78 patients. For all patients, a specially developed technique for the treatment of dry eye syndrome was applied as a series of monthly treatments until there was adequate improvement in dry eye syndrome symptoms by physician judgment, or until patient discontinuation. RESULTS: Primary outcomes included change in tear breakup time, self-reported patient satisfaction, and adverse events. Physician-judged improvement in dry eye tear breakup time was found for 68 of 78 patients (87%) with seven treatment visits and four maintenance visits on average (medians), and 93% of patients reported post-treatment satisfaction with degree of dry eye syndrome symptoms. Adverse events, most typically redness or swelling, were found for 13% of patients. No serious adverse events were found. CONCLUSIONS: Although preliminary, study results of intense-pulsed-light therapy treatment for dry eye syndrome caused by meibomian gland dysfunction are promising. A multisite clinical trial with a larger sample, treatment comparison groups, and randomized controlled trials is currently underway.

BACKGROUND: Behavioral family systems therapy (BFST) for adolescents with diabetes has improved family relationships and communication, but effects on adherence and metabolic control were weak. We evaluated a revised intervention, BFST for diabetes (BFST-D). METHODS: One hundred and four families were randomized to standard care (SC) or to 12 sessions of either an educational support group (ES) or a BFST-D over 6 months. Family relationships, adherence, glycosylated hemoglobin (HbA1c), and health care utilization were measured at baseline and after treatment. RESULTS: BFST-D significantly improved family conflict and adherence compared to SC and ES, especially among those with baseline HbA1c > or = 9.0%. BFST-D and ES significantly improved HbA1c compared to SC among those with baseline HbA1c > or = 9.0%. CONCLUSIONS: The revised intervention (BFST-D) improved family conflict and treatment adherence significantly, while both ES and BFST-D reduced HbA1c significantly, particularly among adolescents with poor metabolic control. Clinical translation of BFST-D requires further study.

PURPOSE: To assess neurocognitive and behavioral performance in children with idiopathic epilepsy (CWE, n = 74), their siblings without epilepsy (control, n = 23), and children with migraine (CWM, n = 13), and to identify medical factors related to learning or behavioral problems in CWE. METHODS: Subjects, ages 8-13 years with IQs of >/=80, completed a neurocognitive test battery annually for </=3 years. For CWE, age at seizure onset, most recent EEG results, seizure type, seizure frequency, current antiepileptic drug (AED), and most recent AED serum levels were documented at each visit. RESULTS: CWE and CWM had high rates of grade retention and placement in special education compared with sibling controls. CWE performed worse than controls on numerous neurocognitive variables. These differences persisted over time. CWE with abnormal EEGs scored lower than CWE with normal EEGs on reading and spelling measures, even with comparable IQs. Age at seizure onset, seizure type, and seizure frequency were not related to neurocognitive or behavioral test scores. CWE taking carbamazepine (CBZ) performed better than CWE taking valproate (VPA) on academic achievement measures, although the study lacked controls necessary to assess this finding thoroughly. CWM did not differ from CWE or controls in cognitive or academic achievement skills. CONCLUSIONS: Long-term risk of learning problems exists among CWE as compared with controls, even with normal IQs and well-controlled seizures. Predicting learning problems in CWE based on medical factors remains elusive. Monitoring of educational progress and neurocognitive screening may be most effective in assessing academic risk for CWE.

STUDY DESIGN: Retrospective review. OBJECTIVE: To compare the incidence of and risk factors for proximal junctional kyphosis (PJK) in adolescent idiopathic scoliosis (AIS) following posterior spinal fusion using hook, pedicle screw, or hybrid constructs. SUMMARY OF BACKGROUND DATA: Proximal junctional kyphosis is a recently recognized phenomenon in adults and adolescents after AIS surgery. The postoperative effect on PJK with the use of hooks, hybrid constructs, or screws has not been compared in a multicenter study to date. METHODS: From a multicenter database, the preoperative and 2-year follow-up radiographic measurements from 283 patients with AIS treated with posterior spinal fusion using hooks (group 1, n = 51), hybrid constructs (group 2, n = 177), pedicle screws (group 3, n = 37), and pedicle screws with hooks only at the top level (group 4, n = 18) were compared. RESULTS: The average proximal level kyphosis at 2 years after surgery was 8.2 degrees (range -1 to 18) in the all screw constructs, representing a significant increase when compared with hybrid and all hook constructs, 5.7 degrees (P = 0.02) and 5.0 degrees (P = 0.014), respectively. Conversely, average postoperative T5-T12 kyphosis was significantly less (P = 0.016) in the screw group compared with the all hook group. Of potential interest, but currently not statistically significant, was the trend towards a decrease in proximal kyphosis in constructs with all pedicle screws except hooks at the most cephalad segment, 6.4 degrees . The incidence of PJK (assuming PJK is a kyphotic deformity greater than 15 degrees ) was 0% in group 1, 2.3% in group 2, 8.1% in group 3, and 5.6% in group 4 (P = 0.18). Patients with PJK had an increased body mass index compared with those who did not meet criteria for PJK (P = 0.013). CONCLUSION: Adjacent level proximal kyphosis was significantly increased with pedicle screws, but the clinical significance of this is unclear. A potential solution is the substitution of hooks at the upper-instrumented vertebrae, but further investigation is required.

Growth hormone is produced by the somatotroph cells of the anterior pituitary. Its secretion is stimulated by growth hormone–releasing hormone and inhibited by somatostatin, which are both produced by the hypothalamus. Growth hormone secretion is pulsatile, and the amplitude of the pulses is greatest at night. Twenty-four-hour growth hormone secretion is maximal during puberty and declines gradually thereafter in both women and men. Growth hormone acts by binding to receptors on liver cells and other cells. One growth hormone molecule binds to two receptor molecules on the target cell, initiating a cascade of events that results in the secretion of . . .

OBJECTIVE: To describe the short-term results of a controlled trial of Behavioral Family Systems Therapy (BFST) for families of adolescents with diabetes. METHODS: We randomized 119 families of adolescents with diabetes to 3 months' treatment with either BFST, an education and support Group (ES), or current therapy (CT). Family relationships, psychological adjustment to diabetes, treatment adherence and diabetic control were assessed at baseline, after 3 months of treatment (reported here), and 6 and 12 months later. RESULTS: Compared with CT and ES, BFST yielded more improvement in parent-adolescent relations and reduced diabetes-specific conflict. Effects on psychological adjustment to diabetes and diabetic control were less robust and depended on the adolescent's age and gender. There were no effects on treatment adherence. CONCLUSIONS: BFST yielded some improvement in parent-adolescent relationships; its effects on diabetes outcomes depended on the adolescent's age and gender. Factors mediating the effectiveness of BFST must be clarified.

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.

Patient satisfaction is an individual's cognitive evaluation of, and emotional reaction to, his or her health-care experience. This concept is increasing in importance as survey data are being used by health-care facilities for self-assessment, accreditation requirements, and compensation formulas. High patient satisfaction is associated with increased market share, financial gains, decreased malpractice claims, and improved reimbursement rates. Modifiable factors that contribute to satisfaction include physician-patient communication, the setting of appropriate expectations, minimization of waiting times, and provision of continuity of care. There are also factors that are less amenable to change, including chronic illness, opioid dependence, and sociodemographic status. Satisfaction with a surgical outcome differs from satisfaction with an office visit. Accurate expectations and patient-reported outcome measures are important determinants of satisfaction after a surgical procedure. Physicians can improve patient satisfaction in their practice by understanding the implications of satisfaction and the predictors of success.

BACKGROUND: This study evaluated the CGRP receptor antagonist MK-3207 for acute treatment of migraine. METHODS: Multicenter, double-blind, randomized, placebo-controlled, parallel-group, two-stage adaptive study with two interim efficacy analyses to facilitate optimal dose selection. Migraine patients were initially randomized to MK-3207 2.5, 5, 10, 20, 50 and 100 mg or placebo to treat a moderate/severe migraine. One or more doses were to be discontinued based on the first interim analysis and a lower or higher dose could be added based on the second interim analysis. The primary endpoint was two-hour pain freedom. RESULTS: A total of 547 patients took study medication. After the first interim analysis, the two lowest MK-3207 doses (2.5, 5 mg) were identified as showing insufficient efficacy. Per the pre-specified adaptive design decision rule, only the 2.5-mg group was discontinued and the five highest doses (5, 10, 20, 50, 100 mg) were continued into the second stage. After the second interim efficacy analysis, a 200 mg dose was added due to insufficient efficacy at the top three (20, 50, 100 mg) doses. A positive dose-response trend was demonstrated when data were combined across all MK-3207 doses for two-hour pain freedom (p < .001). The pairwise difference versus placebo for two-hour pain freedom was significant for 200 mg (p < .001) and nominally significant for 100 mg and 10 mg (p < .05). The incidence of adverse events appeared comparable between active treatment groups and placebo, and did not appear to increase with increasing dose. CONCLUSIONS: MK-3207 was effective and generally well tolerated in the acute treatment of migraine.

UNLABELLED: The control of the onset of puberty involves the complex interaction of pituitary and gonadal hormones. At a preprogrammed time in a child's life there is an increase in the amplitude of GnRH pulses which triggers a cascade of events including increases in the amplitude of FSH and LH pulses, followed by marked increases in gonadal sex steroidal output, which in turn increases growth hormone (GH) and insulin-like growth factor-1 (IGF-1) production. Evidence suggests that there is an integral interaction between the endogenous opiate system and the hypothalamic-pituitary-gonadal axis, at least in the later stages of puberty in the male. Both androgenic and estrogenic hormones markedly increase GH production rates as measured by deconvolution models in the prepubertal human, and compelling data strongly suggest that it is indeed the estrogen which controls the feedback amplification of GH production during puberty even in the male. It appears that the prepubertal gonad is actively producing sex hormones which might be important in the control of GH production since early childhood. The translation of these neuroendocrine rhythms into distal metabolic actions is also reviewed. Utilizing isotopic tracer infusions of the essential amino acid leucine, studies clearly show a selective stimulation of whole body protein synthesis by both GH and IGF-1. GH, IGF-1 and androgenic hormones all increase in puberty, stimulating whole body protein anabolism during that period. However, we observed no protein-anabolic effect in the hypogonadal female given increasing doses of estrogen. The latter suggests that at least as it pertains to whole body protein effects, the action of androgens is probably mediated via the androgen and not the estrogen receptor, in clear distinction from the estrogen-mediated effects of androgens on the neuroendocrine axis. Calcium absorption and retention are also positively affected by the androgens as shown by significant increases in calcium absorption and retention after the administration of testosterone to the prepubertal male. This suggests an important role of sex steroidal hormones in the mineralization of the skeleton. IN CONCLUSION: GH, IGF-1 and sex steroids all markedly increase during puberty and their actions are amplified mutually as they control growth, increase muscle mass and affect the mineralization of the skeleton. The dichotomy of androgen and estrogen effects in the male and female may regulate the differential timing of the onset of puberty and final height in the two sexes. The synergistic actions of these anabolic hormones appear to be most significant during the finite years of puberty.

RATIONALE: Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes. OBJECTIVE: To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in patients with asthma receiving montelukast for 6 mo who participated in a clinical trial. METHODS: Polymorphisms were typed using Sequenom matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array spectrometry and published methods; haplotypes were imputed using single nucleotide polymorphism-expectation maximization (SNP-EM). Analysis of variance and logistic regression models were used to test for changes in outcomes by genotype. In addition, chi(2) and likelihood ratio tests were used to test for differences between groups. Case-control comparisons were analyzed using the SNP-EM Omnibus likelihood ratio test. MEASUREMENTS: Outcomes were asthma exacerbation rate and changes in FEV(1) compared with baseline. RESULTS: DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV(1) (p < 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found. CONCLUSIONS: Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response.

INTRODUCTION: High-flow nasal cannula therapy (HFNC) has been shown to be more effective than continuous positive airway pressure (CPAP) in reducing intubations and ventilator days. HFNC likely provides mechanisms to support respiratory efficiency beyond application of distending pressure. We reason that HFNC washout of nasopharyngeal dead space impacts CO(2) removal along with oxygenation. The aim of this study was to demonstrate the flow dependence of CO(2) reduction and improved oxygenation during HFNC and the dependence on leak around the nasal prongs. MATERIALS AND METHODS: Neonatal piglets (n=13; 2-6 kg) were injured with IV oleic acid and supported with HFNC at 2 through 8 L/min. High and low leak around the nasal prongs was accomplished by using single and double prong cannulae, respectively. Measurement of hemodynamic, respiratory and blood gas parameters were made at each setting following 10 min for physiologic equilibration. Tracheal pressures were recorded by transmural catheters. RESULTS: With HFNC, CO(2) trended downward in a flow-dependent manner independent of leak. Oxygenation and tracheal pressures increased in a flow-dependent manner with the greatest effect during double prong. At 8 L/min, tracheal pressures did not exceed 6 ± 1 cmH(2) O. CONCLUSIONS: HFNC improves gas exchange in a flow-dependent manner; double prong had greater impact on O(2;) single prong had greater impact on CO(2) elimination.

A novel perspective of the function of carotenoids and carotenoid-derived products - including, but not restricted to, the retinoids - is emerging in recent years which connects these compounds to the control of adipocyte biology and body fat accumulation, with implications for the management of obesity, diabetes and cardiovascular disease. Cell and animal studies indicate that carotenoids and carotenoids derivatives can reduce adiposity and impact key aspects of adipose tissue biology including adipocyte differentiation, hypertrophy, capacity for fatty acid oxidation and thermogenesis (including browning of white adipose tissue) and secretory function. Epidemiological studies in humans associate higher dietary intakes and serum levels of carotenoids with decreased adiposity. Specifically designed human intervention studies, though still sparse, indicate a beneficial effect of carotenoid supplementation in the accrual of abdominal adiposity. The objective of this review is to summarize recent findings in this area, place them in physiological contexts, and provide likely regulatory schemes whenever possible. The focus will be on the effects of carotenoids as nutritional regulators of adipose tissue biology and both animal and human studies, which support a role of carotenoids and retinoids in the prevention of abdominal adiposity.