Optimizing care for children with difficult-to-treat and severe asthma through specialist paediatric asthma centres: expert practical experience and advice.

Severe asthma in children carries an unacceptable treatment burden, yet its rarity means clinical experience in treating it is limited, even among specialists. Practical guidance is needed to support clinical decision-making to optimize treatment for children with this condition.This modified Delphi convened 16 paediatric pulmonologists and allergologists from northern Europe, all experienced in treating children with severe asthma. Informed by interviews with stakeholders involved in the care of children with severe asthma (including paediatricians, nurses and carers), and an analysis of European guidelines, the experts built a consensus focused on the gaps in existing guidance. Explored were considerations for optimizing care for patients needing biologic treatment, and for selecting home or hospital delivery of biologics. This consensus is aimed at clinicians in specialist centres, as well as general paediatricians, paediatric allergologists and paediatric pulmonologists who refer children with the most severe asthma to specialist care. Consensus is based on expert opinion and is intended for use alongside published guidelines.Our discussions revealed three key facets to optimizing care. Firstly, early asthma detection in children presenting with wheezing and/or dyspnoea is vital, with a low threshold for referral from primary to specialist care. Secondly, children who may need biologics should be referred to and managed by specialist paediatric asthma centres; we define principles for the specialist team members, tests, and expertise necessary at such centres, as well as guidance on when homecare biologics delivery is and is not appropriate. Thirdly, shared decision-making is essential at all stages of the patient's journey: clear, concise treatment plans are vital for patient/carer self-management, and structured processes for transition from paediatric to adult services are valuable. The experts identified the potential for specialist paediatric asthma nurses to play a significant role in facilitating multidisciplinary working.Through this project is agreed a framework of practical advice to optimize the care of children with severe asthma. We encourage clinicians and policymakers to implement this practical advice to enhance patient care.

Aminoglycoside-induced sensorineural hearing loss in pediatric cystic fibrosis patients: A retrospective cohort study.

Background: Pulmonary infections by gram-negative organisms are important in cystic fibrosis (CF). Aminoglycosides (AG) are often part of the treatment regimen. However, they are a well-known cause of ototoxicity. Even minimal hearing impairment in children could have a future impact on functional well-being.We aimed to investigate the progression of sensorineural hearing loss (SNHL) over several years in pediatric CF patients, and to identify risk factors, such as the use of AG, including both intravenous (IV) and inhaled AG. Methods: Retrospective analyses of patient records from children and adolescents followed up at the CF clinic of the Antwerp University Hospital, Belgium, were performed. We collected data on age, sex, pure-tone audiometry, and the use of AG. Descriptive and binary logistic regression analyses, and if indicated generalized estimating equations (GEE) analyses were performed. Results: Forty pediatric patients were enrolled in the study taking part from 2013 to 2020. Pure-tone audiometry revealed an important rate of SNHL over several years, with a prevalence of 29 % for high-frequency SNHL (i.e. 8 kHz). Increasing age was identified as a significant risk factor for the development of SNHL at 8 kHz if 5 or more IV AG courses (p = 0.01) were reported or when IV AG were combined with inhaled AG (p = 0.002). Conclusions: Age combined with the use of IV AG (≥5 courses or in combination with inhaled AG) are predictive for developing high-frequency SNHL (i.e. 8 kHz). We suggest routine annual hearing screening (incl. high-frequency thresholds) in CF patients, starting from childhood.

Hippo signaling instructs ectopic but not normal organ growth.

The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.

Unintentional combining enzalutamide with a moderate CYP2C8 inhibitor in a patient with metastatic castration-resistant prostate cancer: a case report.

BACKGROUND: Enzalutamide, registered for the treatment of metastatic castration-resistant prostate cancer (mCRPC), is an inducer of multiple CYP-enzymes. Enzalutamide itself is mainly converted by CYP2C8 to the active metabolite N-desmethylenzalutamide (NDME). Due to a pharmacokinetic interaction, combining enzalutamide with a moderate CYP2C8 inhibitor might result in higher enzalutamide concentrations. Addressing this interaction is challenging since pharmacokinetic data are missing. CASE PRESENTATION: We present a case of a Caucasian male with mCRPC who was treated with enzalutamide and a moderate CYP2C8 inhibitor, clopidogrel, concomitantly. Plasma trough levels (Ctrough) of enzalutamide and its active metabolite N-desmethylenzalutamide (NDME) were determined and compared when treated with and without clopidogrel. The sum concentration of enzalutamide and NDME was not affected by coadministration of a moderate CYP2C8 inhibitor. Both treatments were well tolerated and no major side effect were observed. CONCLUSION: This case report shows that enzalutamide can be safely prescribed while cotreated with a moderate CYP2C8-inhibitor, without reducing the dose. More research is warranted to make a statement about the effect of enzalutamide on clopidogrel.

Effect of body weight on upper airway findings and treatment outcome in children with obstructive sleep apnea.

OBJECTIVE/BACKGROUND: Surgical interventions for obstructive sleep apnea (OSA) are less effective in obese than in normal-weight children. However, the mechanisms that underpin this relationship are not fully understood. Therefore, this study aimed to explore how body weight influences upper airway collapse and treatment outcome in children with OSA. METHODS: We conducted a retrospective analysis of prospectively collected data on polysomnography, drug-induced sleep endoscopy (DISE), and treatment outcome in otherwise healthy children with OSA. Associations between body mass index (BMI) z-score and upper airway collapse during DISE were assessed using logistic regression modelling. Treatment success was defined as obstructive apnea-hypopnea index (oAHI) < 5 events/hour and cure as oAHI < 2 events/hour with obstructive apnea index < 1 event/hour. RESULTS: A total of 139 children were included [median (Q1─Q3); age 4.5 (3.1─8.4) years; BMI z-score 0.3 (-0.8 to 1.4); oAHI 10.8 (6.8─18.0) events/hour]. Twenty-five of them were overweight and 21 were obese. After adjusting for age and history of upper airway surgery, BMI z-score was significantly correlated with circumferential upper airway collapse during DISE (odds ratio 1.67; 95% confidence interval 1.12─2.65; P = 0.011). Outcome of DISE-directed treatment was similar in normal-weight (success: 91.4%; cure: 78.5%), overweight (success: 88.0%; cure: 80.0%), and obese (success: 90.5%; cure: 76.5%) children. Children with circumferential collapse responded better to continuous positive airway pressure than to (adeno)tonsillectomy. CONCLUSION: Increasing body weight is associated with circumferential upper airway collapse during DISE and, accordingly, may require treatment strategies other than (adeno)tonsillectomy.

Lung imaging in bronchopulmonary dysplasia: a systematic review.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a common complication of preterm birth. Both historically and in current practice, radiologic evaluation of the lungs has an important role in assessing disease severity and complications. AIM: To provide an overview of imaging techniques for detecting lung abnormalities in patients with BPD in all age ranges. METHODS: A systematic literature search was conducted in PubMed, Web of Science and the Cochrane Library. Records were screened by title and abstract and then by full text. A total of 37 records were selected and included in this qualitative literature overview. RESULTS: Computed tomography (CT) was the most commonly used imaging modality, followed by chest radiography and magnetic resonance imaging (MRI). Several qualitative and quantitative scoring systems were presented and most showed good correlation with BPD severity. The association with functional and clinical outcomes was only rarely reported, showing varying correlation with spirometry results and respiratory exacerbations. MRI is an upcoming imaging technique for BPD that is technically feasible, showing clear differences in the lung parenchyma of patients with BPD. CONCLUSION: Several imaging and scoring methods indicate that lung imaging continues to play a role in BPD care. Standardization and correlation with functional and clinical outcomes will become increasingly important for further research.

Positional obstructive sleep apnea in children: prevalence and risk factors.

PURPOSE: Positional (supine dependent) obstructive sleep apnea (POSA) affects about 55% of adults with obstructive sleep apnea (OSA). We aimed to study the prevalence and risk factors for POSA in children. METHODS: Cross-sectional analysis of data obtained in 171 children with moderate to severe OSA confirmed by polysomnography (PSG) performed over a 2-year period. POSA is defined by an obstructive apnea-hypopnea index (oAHI) in the supine position ≥ 2× oAHI in the non-supine position. RESULTS: The overall prevalence of POSA was 18.7%. Children with POSA were significantly older (p < 0.001), had a higher prevalence of obesity (p = 0.04), a lower tonsil score (p = 0.049), and less severe OSA (lower oAHI) (p = 0.02) compared to children without POSA, while age was the only significant independent predictor of POSA. The ratio AHI supine to AHI non-supine was not significantly higher during REM than during NREM sleep in children with POSA. CONCLUSIONS: POSA is less common in children compared to adults and the prevalence of POSA increases with age. Although OSA worsens during REM sleep, this was not observed for POSA. Future studies should investigate the prevalence of POSA in specific subgroups and upper airway characteristics of POSA in children.

The Optiflow™ interface for chronic CPAP use in children.

Continuous positive airway pressure (CPAP) is being increasingly used in children of all age ranges. The limited number of commercially available masks especially in infants and young children may complicate its use and compliance. In this report, we describe our experience with the use of the Optiflow™ (Fisher and Paykel Healthcare) Nasal Cannula attached to a regular CPAP device in the setting of chronic CPAP use. This interface consists of a nasal cannula and was originally designed for the delivery of high-flow oxygen therapy. We could show an objective improvement in breathing parameters in several children selected for CPAP mainly because of obstructive sleep apnea syndrome (OSAS). However, this interface cannot be used for bilevel non-invasive ventilation due to insufficient triggering.

Sleep disorders during childhood: a practical review.

Sleep disorders are a common problem during childhood. The consequences are variable, and sleep disorders can influence medical, psychological and developmental aspects of the growing child. It is important to recognize sleep disorders and to treat them correctly. We discuss common sleep disorders during childhood using the 3rd edition of the International Classification of Sleep Disorders. We analyze the different sleep disorders from a clinical approach and provide an overview of adequate treatment options.Conlusion: This review discusses common sleep disorders during childhood using the 3rd edition of the International Classification of Sleep Disorders. We analyze the different sleep disorders from a clinical approach and provide an overview of adequate treatment options. What is known: • Sleep disorders are a common problem during childhood. • The consequences are variable, and sleep disorders can influence medical, psychological, and developmental aspects of the growing child. What is new: • Pediatricians should routinely screen for sleep and sleep disorders. • It is important to recognize sleep disorders and to treat them correctly.

Drug-induced sedation endoscopy in surgically naïve infants and children with obstructive sleep apnea: impact on treatment decision and outcome.

PURPOSE: Adenotonsillectomy (AT) is the first-line treatment for obstructive sleep apnea (OSA) in children irrespective of clinical upper airway (UA) findings. We aimed to investigate whether drug-induced sedation endoscopy (DISE) changes treatment decision and outcome in otherwise healthy children and infants with OSA. METHODS: Retrospective analysis of prospectively collected data on polysomnography, DISE, and treatment in surgically naïve, otherwise healthy infants (n = 34) and children (n = 75) with OSA. Treatment success is defined as post-treatment obstructive apnea/hypopnea index (oAHI) < 5 h-5-1, and cure is defined as oAHI < 2 h-1. RESULTS: Based upon UA findings during DISE, AT was performed in 22 infants and 57 children. oAHI improved from 16.5 h-1 (8.1-28.3) to 0.8 h-1 (0.3-4.2) (p = 0.01) in infants and from 28.6 h-1 (23.4-34.9) to 0.7 h-1 (0.4-1.8) (p < 0.001) in children. AT was successful in 84.2% of infants and 91.4% of children. A cure was obtained in 68.4% of infants and 78.7% of children. DISE changed the treatment decision in 1/3rd of infants and 1/4th of children, and they did not undergo AT. In the non-AT group, isolated adenoidectomy/tonsillectomy or non-surgical treatment was successful in 86.6% of children and in 100% of infants. Cure was achieved in 66.6% of children and 75% of infants. CONCLUSIONS: DISE performed in otherwise healthy and surgically naïve infants and children with OSA altered the therapeutic decision making in up to 1/3rd to 1/4th of the cases and resulted in comparable treatment outcomes as standard treatment by AT. The present data suggest that DISE may provide individually tailored treatment of OSA in otherwise healthy infants and children.

Functionality based method for simultaneous isolation of rodent hepatic sinusoidal cells.

Chronic liver disease is the result of long term exposure to viruses or toxins such as alcohol, fat and drugs, and forms the basis for the development of liver fibrosis and primary liver cancer. In vitro and in vivo models are key to study the pathways involved in chronic liver disease and for the development of therapeutics. 3D co-culture systems are becoming the in vitro standard, which requires freshly isolated primary hepatic cells. We developed a novel isolation method to simultaneously isolate liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs) and hepatic stellate cells (HSCs). The method exploits the scavenging activity of LSECs, the phagocytic capacity of KCs and the retinoid content of HSCs in vivo to enable direct processing by fluorescence-activated cell sorting without additional antibody binding and washing steps. UFACS3, for UV-FACS-based isolation of 3 non-parenchymal liver cell types, yields functional and pure LSECs (98 ± 1%), KCs (98 ± 1%) and HSCs (97 ± 3%), with less hands-on time from healthy and diseased rodent livers. This novel approach allows a fast and effective combined isolation of sinusoidal cells for further analysis.

Telomere attrition and growth: a life-history framework and case study in common terns.

The relationship between growth and age-specific telomere length, as a proxy of somatic state, is increasingly investigated, but observed patterns vary and a predictive framework is lacking. We outline expectations based on the assumption that telomere maintenance is costly and argue that individual heterogeneity in resource acquisition is predicted to lead to positive covariance between growth and telomere length. However, canalization of resource allocation to the trait with a larger effect on fitness, rendering that trait relatively invariant, can cause the absence of covariance. In a case study of common tern (Sterna hirundo) chicks, in which hatching order is the main determinant of variation in resource acquisition within broods, we find that body mass, but not telomere length or attrition, varies with hatching order. Moreover, body mass and growth positively predict survival to fledging, whereas telomere length and attrition do not. Using a novel statistical method to quantify standardized variance in plasticity, we estimate between-individual variation in telomere attrition to be only 12% of that of growth. Consistent with the relative invariance of telomere attrition, we find no correlation between age-specific body mass or growth and telomere attrition. We suggest that common tern chicks prioritize investment in long-term somatic state (as indicated by canalization of telomere maintenance) over immediate survival benefits of growth as part of an efficient brood reduction strategy that benefits the parents. As such, interspecific variation in the growth-telomere length relationship may be explained by the extent to which parents benefit from rapid mortality of excess offspring.

Drug-induced sedation endoscopy in children <2 years with obstructive sleep apnea syndrome: upper airway findings and treatment outcomes.

Few data are available about the pattern of upper airway (UA) obstruction in children <2 years with obstructive sleep apnea syndrome (OSAS). Also, the role of adenoidectomy versus adenotonsillectomy (AT) is poorly defined in this age group. We performed drug-induced sedation endoscopy (DISE) in young OSAS children to investigate the pattern of UA obstruction and the value of DISE in therapeutic decision making. Retrospective analysis of ≤2-year-old children undergoing DISE-directed UA surgery. OSAS severity and the treatment outcomes were documented by polysomnography. Data are available for 28 patients, age 1.5 years (1.3-1.8), BMI-z score 0.5 (-0.7 to 1.3) with severe OSAS, obstructive apnea/hypopnea index (oAHI) 13.8/hr (7.5-28.3). All but 3 had (>50%) obstruction at the level of the adenoids, and all but 5 had (>50%) tonsillar obstruction. DISE-directed treatment consisted of adenoidectomy (n = 4), tonsillectomy (n = 1), and AT (n = 23). There was a significant improvement in respiratory parameters. Twenty children (71.4%) had a postoperative oAHI <2/hr. None had palatal or tongue base obstruction. Five children had a circumferential UA narrowing (hypotonia), 2 of them had residual OSAS. DISE showed a collapse of the epiglottis in 6 and late-onset laryngomalacia in 4. These findings did not affect surgical outcome. Adenotonsillar hypertrophy is the major cause of UA obstruction, and DISE-directed UA surgery was curative in 71,4% of children ≤2 years. We suggest that DISE may be helpful in surgical decision making. Circumferential UA narrowing may result in less favorable surgical outcomes.

Adenotonsillectomy to treat obstructive sleep apnea: Is it enough?

Although adenotonsillectomy is the first line treatment for children with obstructive sleep apnea syndrome (0SAS),1 improvement in objectively documented outcomes is often inadequate and a substantial number of children have residual disease. Early recognition and treatment of children with persistent OSAS is required to prevent long-term morbidity. The management of these children is frequently complex and a multidisciplinary approach is required as most of them have additional risk factors for OSAS and comorbidities. In this paper, we first provide an overview of children at risk for persistent disease following adenotonsillectomy. Thereafter, we discuss different diagnostic modalities to evaluate the sites of persistent upper airway obstruction and the currently available treatment options. Pediatr Pulmonol. 2017;52:699-709. © 2016 Wiley Periodicals, Inc.

Stabilizing survival selection on presenescent expression of a sexual ornament followed by a terminal decline.

Senescence is a decrease in functional capacity, increasing mortality rate with age. Sexual signals indicate functional capacity, because costs of ornamentation ensure signal honesty, and are therefore expected to senesce, tracking physiological deterioration and mortality. For sexual traits, mixed associations with age and positive associations with life expectancy have been reported. However, whether these associations are caused by selective disappearance and/or within-individual senescence of sexual signals, respectively, is not known. We previously reported that zebra finches with redder bills had greater life expectancy, based on a single bill colour measurement per individual. We here extend this analysis using longitudinal data and show that this finding is attributable to terminal declines in bill redness in the year before death, with no detectable change in presenescent redness. Additionally, there was a quadratic relationship between presenescent bill colouration and survival: individuals with intermediate bill redness have maximum survival prospects. This may reflect that redder individuals overinvest in colouration and/or associated physiological changes, while below-average bill redness probably reflects poorer phenotypic quality. Together, this pattern suggests that bill colouration is defended against physiological deterioration, because of mate attraction benefits, or that physiological deterioration is not a gradual process, but accelerates sharply prior to death. We discuss these possibilities in the context of the reliability theory of ageing and sexual selection.

Biocompatibility of single-walled carbon nanotube composites for bone regeneration.

OBJECTIVES: The purpose of this study was to evaluate in vivo biocompatibility of novel single-walled carbon nanotubes (SWCNT)/poly(lactic-co-glycolic acid) (PLAGA) composites for applications in bone and tissue regeneration. METHODS: A total of 60 Sprague-Dawley rats (125 g to 149 g) were implanted subcutaneously with SWCNT/PLAGA composites (10 mg SWCNT and 1gm PLAGA 12 mm diameter two-dimensional disks), and at two, four, eight and 12 weeks post-implantation were compared with control (Sham) and PLAGA (five rats per group/point in time). Rats were observed for signs of morbidity, overt toxicity, weight gain and food consumption, while haematology, urinalysis and histopathology were completed when the animals were killed. RESULTS: No mortality and clinical signs were observed. All groups showed consistent weight gain, and the rate of gain for each group was similar. All groups exhibited a similar pattern for food consumption. No difference in urinalysis, haematology, and absolute and relative organ weight was observed. A mild to moderate increase in the summary toxicity (sumtox) score was observed for PLAGA and SWCNT/PLAGA implanted animals, whereas the control animals did not show any response. Both PLAGA and SWCNT/PLAGA showed a significantly higher sumtox score compared with the control group at all time intervals. However, there was no significant difference between PLAGA and SWCNT/PLAGA groups. CONCLUSIONS: Our results demonstrate that SWCNT/PLAGA composites exhibited in vivo biocompatibility similar to the Food and Drug Administration approved biocompatible polymer, PLAGA, over a period of 12 weeks. These results showed potential of SWCNT/PLAGA composites for bone regeneration as the low percentage of SWCNT did not elicit a localised or general overt toxicity. Following the 12-week exposure, the material was considered to have an acceptable biocompatibility to warrant further long-term and more invasive in vivo studies. Cite this article: Bone Joint Res 2015;4:70-7.

Rasch analysis of professional behavior in medical education.

The use of students' "consumer feedback" to assess faculty behavior and improve the process of medical education is a significant challenge. We used quantitative Rasch measurement to analyze pre-categorized student comments listed by 385 graduating medical students. We found that students differed little with respect to the number of comments they provided and that their comments indeed form a probabilistic Rasch hierarchy. However, different hierarchies were found across medical departments and faculty. An analysis of these interactions provides valuable, detailed, and quantitative information that can augment qualitative research approaches. In addition, we suggest how the Rasch scaling of student comments can assist researchers in the design and implementation of new faculty evaluation instruments. Finally, the interactions between student and department identified a subset of behaviors that appear to guide and possibly elicit students' comments.

Drug-induced sedation endoscopy in pediatric obstructive sleep apnea syndrome.

AIM: To describe the pattern of upper airway (UA) obstruction during drug-induced sedation endoscopy (DISE) and to evaluate the outcome of DISE-directed treatment. METHODS: Prospective study of DISE in surgically naive obstructive sleep apnea syndrome (OSAS) children without syndromic comorbidity or craniofacial abnormalities. Treatment was individually tailored according to UA findings during DISE and polysomnographic data. Reported values are median (lower-upper quartile). RESULTS: Thirty-seven children aged 4.1 years (2.1-6.0), with body mass index z-score 0.3 (-0.9 to 0.9), and obstructive apnea-hypopnea index (oAHI) 9.0/h (6.1-19.3) were included. Adenotonsillar obstruction was found in 33 cases (89%) as an isolated entity or as part of a multi-level obstruction. These children were treated with adenotonsillectomy (n = 28), adenoidectomy (n = 3), or tonsillectomy (n = 2). The remaining four patients received non-surgical treatment. Pre-postoperative polysomnographic data in 22 patients showed a significant improvement in oAHI from 8.6/h (6.7-20.7) to 1.0/h (0.6-2.0) (P = 0.001). Only two of these 22 children had residual OSAS (oAHI ≥ 5/h), indicating a success rate of 91%. CONCLUSIONS: Based on UA findings during DISE, a non-surgical treatment was proposed for 11% of children. A 91% success rate was obtained in those treated with (adeno)tonsillectomy. These data suggest that DISE may be helpful to identify patients most likely to benefit from UA surgery.

Sleep-disordered breathing and pulmonary function in obese children and adolescents.

OBJECTIVE: Obese children have an increased risk of developing obstructive sleep apnea syndrome (OSAS) compared to normal-weight children. In obese children, OSAS is more frequently associated with oxygen desaturations, which might be caused by pulmonary function abnormalities. Our goal was to investigate the association between OSAS and pulmonary function in obese children and adolescents. METHODS: There were 185 children included and distributed in groups based on their obstructive apnea-hypopnea index (151 controls, 20 mild OSAS, and 14 moderate-to-severe OSAS). All subjects underwent polysomnography and pulmonary function testing. RESULTS: Several differences in pulmonary function were observed between groups. Vital capacity (VC) and forced expired volume in 1s (FEV1) were significantly decreased in patients with moderate-to-severe OSAS, as were expiratory reserve volume (ERV), total lung capacity, and functional residual capacity (FRC). Correlations between FEV1, FRC, and ERV with OSAS severity remained significant independent of the degree of adiposity. Correlations between FEV1/VC and sleep-related respiratory parameters did not persist after correction for adiposity. CONCLUSION: An association between awake pulmonary function and sleep-related respiratory parameters could be observed in our population of obese children. These results suggest that OSAS severity is correlated with a diminished lung function. However, the level of obesity remains an important confounding factor in both OSAS severity and pulmonary function.