Comparison of 3D UTE free-breathing lung MRI with hyperpolarized 129Xe MRI in pediatric cystic fibrosis.

PURPOSE: To compare phase-resolved functional lung (PREFUL) regional ventilation derived from a free breathing 3D UTE radial MRI acquisition to hyperpolarized 129Xe-MRI (Xe-MRI), conventional 2D multi-slice PREFUL MRI, and pulmonary function tests in pediatric cystic fibrosis (CF) lung disease. METHODS: Free-breathing 3D UTE and 2D multi-slice 1H MRI as well as Xe-MRI were acquired in 12 stable pediatric CF patients. Using PREFUL, regional ventilation (RVent) maps were calculated from the free-breathing data. Ventilation defect percentage (VDP) was determined from 3D and 2D RVent maps (2D VDPRVent and 3D VDPRVent, respectively) and Xe-MRI ventilation (VDPXe). VDP was calculated for the whole lung and for eight regions based on left/right, anterior/posterior, and superior/inferior divisions of the lung. Global and regional VDP was compared between the three methods using Bland-Altman analysis, linear mixed model-based correlation, and one-way analysis of variance and multiple comparisons tests. RESULTS: Global 3D VDPRVent, VDPXe, and 2D VDPRVent were all strongly correlated (all R2 > 0.62, p < 0.0001) and showed minimal, non-significant bias (all <2%, p > 0.05). Three dimensional and 2D VDPRVent significantly correlated to VDPXe in most of the separate lung regions (R2 = 0.18-0.74, p < 0.04), but showed lower inter-agreement. The superior/anterior lung regions showed the least agreement between all three methods (all p > 0.12). CONCLUSION: Absolute VDP assessed by 3D UTE PREFUL MRI showed good global agreement with Xe-MRI and 2D multi-slice PREFUL MRI in pediatric CF lung disease. Therefore, 3D UTE PREFUL MRI offers a sensitive and potentially more accessible alternative to Xe-MRI for regional volumetric evaluation of ventilation.

Inter- and intravisit repeatability of free-breathing MRI in pediatric cystic fibrosis lung disease.

PURPOSE: The purpose of this study is to assess the intra- and interscan repeatability of free-breathing phase-resolved functional lung (PREFUL) MRI in stable pediatric cystic fibrosis (CF) lung disease in comparison to static breath-hold hyperpolarized 129-xenon MRI (Xe-MRI) and pulmonary function tests. METHODS: Free-breathing 1-hydrogen MRI and Xe-MRI were acquired from 15 stable pediatric CF patients and seven healthy age-matched participants on two visits, 1 month apart. Same-visit MRI scans were also performed on a subgroup of the CF patients. Following the PREFUL algorithm, regional ventilation (RVent) and regional flow volume loop cross-correlation maps were determined from the free-breathing data. Ventilation defect percentage (VDP) was determined from RVent maps (VDPRVent ), regional flow volume loop cross-correlation maps (VDPCC ), VDPRVent ∪ VDPCC , and multi-slice Xe-MRI. Repeatability was evaluated using Bland-Altman analysis, coefficient of repeatability (CR), and intraclass correlation. RESULTS: Minimal bias and no significant differences were reported for all PREFUL MRI and Xe-MRI VDP parameters between intra- and intervisits (all P > 0.05). Repeatability of VDPRVent , VDPCC , VDPRVent ∪ VDPCC , and multi-slice Xe-MRI were lower between the two-visit scans (CR = 14.81%, 15.36%, 16.19%, and 9.32%, respectively) in comparison to the same-day scans (CR = 3.38%, 2.90%, 1.90%, and 3.92%, respectively). pulmonary function tests showed high interscan repeatability relative to PREFUL MRI and Xe-MRI. CONCLUSION: PREFUL MRI, similar to Xe-MRI, showed high intravisit repeatability but moderate intervisit repeatability in CF, which may be due to inherent disease instability, even in stable patients. Thus, PREFUL MRI may be considered a suitable outcome measure for future treatment response studies.

Timing of Antenatal Corticosteroids for Optimal Neonatal Outcomes: A Markov Decision Analysis Model.

OBJECTIVE: Antenatal corticosteroids (ACSs) are administered to pregnant individuals at high risk of preterm delivery to reduce neonatal morbidity and mortality. ACSs have a limited timeframe of effectiveness, and timing of administration can be difficult because of uncertainty surrounding the likelihood of preterm delivery. The objective of the current study was to design a decision analysis model to optimize the timing of ACS administration and identify important model variables that impact administration timing preference. METHODS: We created a Markov decision analysis model with a base case of a patient at 240 weeks gestation with antepartum hemorrhage. Decision strategies included immediate, delayed, and no ACS administration. Outcomes were based on the neonatal perspective and consisted of lifetime quality adjusted life years (QALYs). Data for model inputs were derived from current literature and clinical recommendations. RESULTS: Our base case analysis revealed a preferred strategy of delaying ACSs for 2 weeks, which maximized QALYs (39.18 lifetime discounted), driven by reduced neonatal morbidity at the expense of 0.1% more neonatal deaths, when compared with immediate ACS administration. Sensitivity analyses identified that, if the probability of delivery within the next week was >6.19%, then immediate steroids were preferred. Other important variables included gestational age, ACS effectiveness, and ACS adverse effects. CONCLUSION: ACS timing involves a trade-off between morbidity and mortality, and optimal timing depends on probability of delivery, gestational age, and risks and benefits of ACSs. Clinicians should carefully consider these factors prior to ACS administration.

Measurement of forces applied using a Macintosh direct laryngoscope compared with a Glidescope video laryngoscope in patients with predictors of difficult laryngoscopy: A randomised controlled trial.

BACKGROUND: In patients with predictive features associated with easy direct laryngoscopy, videolaryngoscoy with the GlideScope has been shown to require less force when compared with Macintosh direct laryngoscopy. OBJECTIVE: The aim of this study was to compare forces applied with Glidescope vs. Macintosh laryngoscopes in patients with predictive features associated with difficult direct laryngoscopy. DESIGN: A randomised study. SETTING: Toronto General Hospital, a university tertiary centre in Canada. PATIENTS: Forty-four patients aged over 18 years, with one or more features of difficult intubation, undergoing elective surgery requiring single-lumen tracheal intubation. INTERVENTION: We measured the force applied to oropharyngeal tissues by attaching three FlexiForce Sensors (A201-25) to the concave surface of Macintosh and GlideScope laryngoscope blades.Anaesthetists or experienced anaesthesia residents performed laryngoscopies with both devices in a randomised sequence. MAIN OUTCOME MEASURES: The primary outcome was peak force. The secondary outcomes were average force and impulse force. The latter is the integral of the force over the time during which the force acted. RESULTS: Complete data were available for 40 individuals. Peak and average forces decreased with GlideScope (17 vs. 21 N, P = 0.03, and 6 vs. 11 N, P < 0.001, respectively). Laryngoscopy time increased with the GlideScope (30 vs. 18 s, P < 0.001), resulting in similar median impulse forces (206 vs. 175 N, P = 0.92). CONCLUSION: GlideScope laryngoscopy resulted in reduced peak and average forces, but as the laryngoscopy duration increased, the product of force and time (impulse force) was similar with both devices. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01814176.

Estimates of primary ciliary dyskinesia prevalence: a scoping review.

Background: Primary ciliary dyskinesia (PCD) is a rare multisystem genetic disease caused by dysfunctional motile cilia. Despite PCD being the second most common inherited airway disease after cystic fibrosis, PCD continues to be under-recognised globally owing to nonspecific clinical features and the lack of a gold standard diagnostic test. Commonly repeated prevalence estimates range from one in 10 000 to one in 20 000, based on regional epidemiological studies with known limitations. The purpose of this scoping review was to appraise the PCD literature, to determine the best available global PCD prevalence estimate and to inform the reader about the potential unmet health service needs in PCD. The primary objective of the present study was to systematically review the literature about PCD prevalence estimates. Methods: A scoping review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) methodology. Included studies estimated PCD prevalence and used cohort, clinical or genomic data. Case reports, conference abstracts, review articles, animal studies or non-English articles were excluded. Results: A literature review identified 3484 unique abstracts; 34 underwent full-text review and eight met the inclusion/exclusion criteria. Seven articles were based on epidemiological studies of specific geographical regions and provided prevalence estimates that ranged from approximately one to 44.1 in 100 000. Only one study estimated global prevalence, using two large genomic databases, and calculated it to be ∼13.2 in 100 000 (based on pathogenic variants in 29 disease-causing genes). Conclusions: A population-based genomic approach for estimating global prevalence has found that PCD is much more prevalent than previously cited in the literature. This highlights the potential unmet health service needs of people living with PCD.

Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare, genetic disease characterized by dysfunctional motile cilia and abnormal mucociliary clearance, resulting in chronic sino-oto-pulmonary disease, neonatal respiratory distress, subfertility, and organ laterality defects. Over the past 2 decades, research and international collaborations have led to an improved understanding of disease prevalence, classic and variable phenotypes, novel diagnostics, genotype-phenotype correlations, long term morbidity, and innovative therapeutics. However, PCD is often underrecognized in clinical settings and the recent analyses of genetic databases suggest that only a fraction of these patients are being accurately diagnosed. Knowledge of significant advancements, from pathophysiology to the expanded range of clinical manifestations, will have important clinical impacts. These may include increasing disease recognition, improving diagnostic testing and management, and establishing an adequate pool of affected patients to enroll in upcoming clinical therapeutic trials. The objective of this state-of-the-art review is for readers to gain a greater understanding of the clinical spectrum of motile ciliopathies, cutting-edge diagnostic practices, emerging genotype-phenotype associations, and currently accepted management of people with PCD.

Mortality of Pediatric Surgical Lung Biopsies in Ontario, Canada, 2000-2019.

Rationale: Surgical lung biopsies are often required for the definitive diagnosis of nonmalignant pediatric diffuse lung diseases; however, the literature on mortality after surgical lung biopsy in pediatric patients is sparse. Objectives: To determine the 30-day postoperative mortality rate after surgical lung biopsies for nonmalignant lung disease in pediatric patients in Ontario, Canada, and to identify risk factors associated with mortality. Methods: We performed an observational cohort study using population-based health administrative data available from ICES in Ontario, Canada, from 2000 to 2019. Cases were identified using the Canadian Classification of Health Interventions. Inclusion criteria were first surgical lung biopsies between 2000 and 2019 and age <18 years. Individuals with lung cancer, lung transplant, or missing data were excluded. A multivariable logistic regression model with generalized estimating equation was used to estimate the 30-day odds of mortality after surgical lung biopsy and to identify patient characteristics associated with increased mortality while accounting for clustering by hospital. Results: We identified 1,474 pediatric patients who underwent surgical lung biopsy in Ontario between 2000 and 2019. The overall mortality rates decreased over the study duration from 6.6% (2000-2004) to 3.0% (2015-2019). The study cohort for multivariate analyses consisted of 1,342 patients who had complete data. The pediatric mortality 30 days after surgical lung biopsy was 5.1% but was <1% in elective cases. Risk factors for increased mortality included open surgical lung biopsy (vs. video-assisted) (odds ratio [OR], 13.13; 95% confidence interval [CI], 3.76, 45.87; P < 0.001), nonelective procedure (OR, 11.74; 95% CI, 3.51, 39.27; P < 0.001), younger age (<3 mo) (OR, 6.04; 95% CI, 2.40, 15.22; P < 0.001), and higher comorbidity score (OR, 1.15; 95% CI, 1.05, 1.26; P = 0.003). Conclusions: Pediatric mortality postsurgical lung biopsy is not insignificant, particularly in nonelective procedures. Other important risk factors to consider when pursuing pathologic diagnosis include surgical approach, younger age, and higher comorbidity.

Bronchodilator responsiveness in children with primary ciliary dyskinesia.

Background: Reversible airway obstruction is common in children with primary ciliary dyskinesia. However, the diagnostic value of adding bronchodilator (BD) response testing to routine spirometry is unclear. Methods: This is a retrospective analysis of pulmonary function test results obtained from children with primary ciliary dyskinesia seen as outpatients at the Hospital for Sick Children, Toronto. Spirometry results were collected for every appointment with BD response testing ("Visit", with pre-BD and post-BD measurements) as well as for the previous ("Baseline") and following ("Follow-up") encounters. Results: A positive BD response was seen in 86 out of 474 (18.1%) of the pulmonary function tests from 82 children with primary ciliary dyskinesia. BD responsiveness was associated with a significant absolute change (±sd) in % predicted forced expiratory volume in 1 s (FEV1) from Baseline to Visit pre-BD (-6.5±10.3%, p<0.001), but not from Baseline to Follow-up (0.4±10.8, p=0.757). Antimicrobial therapy was initiated more commonly following a Visit with a positive BD response (OR 3.8, 95% CI 2.2-6.6) compared to no BD response. Children with a positive BD response had a greater annual decline in FEV1 % predicted compared to those with no BD response (-0.9% per year versus -0.5% per year, p<0.001). The annual decline in FEV1 % predicted was greater in children with multiple compared to one measured positive BD responses (-1.3% per year versus -0.6% per year, p<0.001) and in those not treated with antibiotic therapy following a positive BD response compared to those treated with antibiotics (-1.1% versus -0.6%, p<0.001). Conclusion: A positive BD response in children with primary ciliary dyskinesia may help identify those at risk for accelerated lung disease progression.

Efficacy of Antibiotic Eradication Therapy of Early Pseudomonas aeruginosa Infection in Children with Primary Ciliary Dyskinesia.

Rationale: Chronic infection with Pseudomonas aeruginosa (PsA) negatively impacts lung disease in patients with primary ciliary dyskinesia (PCD). There is currently limited evidence regarding the efficacy of PsA antibiotic eradication therapy (AET) in children with PCD. Objectives: To assess the effectiveness of AET of early PsA infection in children with PCD. Methods: This retrospective study included pediatric patients with a confirmed PCD diagnosis according to the American Thoracic Society guidelines at the Hospital for Sick Children between 2010 and 2022. Children with newly acquired PsA infection underwent AET using a stepwise protocol. The protocol included the following steps: step 1, 28 days of tobramycin inhalation solution (TIS); step 2, repeat TIS if culture positive after step 1; and step 3, 14 days of intravenous antibiotics followed by 28 days of TIS if culture positive after step 2. Step 3 was also used for patients who presented with pulmonary exacerbation symptoms. The main outcome was a PsA-negative culture result based on the microbiological results of the first culture after completion of each step of treatment. Results: During the study period, 31 children had a new PsA infection and underwent AET. Of the 27 children who had been asymptomatic at the time of the PsA infection, negative PsA culture results were achieved in 20 (74%) of 27, 1 (14%) of 7, and 5 (83%) of 6 after steps 1, 2, and 3 of AET, respectively. All four symptomatic patients who initially were treated with step 3 had successful clearance of PsA. The overall cumulative success rate of the protocol for negative culture results after AET was 97% (30 of 31). For patients in whom AET was successful, the probability of staying PsA free for at least 1 year was 70%. Conclusions: AET for early PsA infection is highly effective in PCD, with sustained efficacy in most individuals. These data suggest that AET should be considered in all children with PCD who have early PsA infection.

Situs Ambiguus Is Associated With Adverse Clinical Outcomes in Children With Primary Ciliary Dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare disorder of motile cilia associated with situs abnormalities. At least 12% of patients with PCD have situs ambiguus (SA), including organ laterality defects falling outside normal arrangement (situs solitus [SS]) or mirror image inversion (situs inversus totalis [SIT]). RESEARCH QUESTION: Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT? STUDY DESIGN AND METHODS: This cross-sectional, multicenter study evaluated participants aged 21 years or younger with PCD. Participants were classified as having SA, including heterotaxy, or not having SA (SS or SIT). Markers of disease severity were compared between situs groups, adjusting for age at enrollment and severe CCDC39 or CCDC40 genotype, using generalized linear models and logistic and Poisson regression. RESULTS: In 397 participants with PCD (mean age, 8.4 years; range, 0.1-21), 42 patients were classified as having SA, including 16 patients (38%) with complex cardiovascular malformations or atrial isomerism, 13 patients (31%) with simple CVM, and 13 patients (31%) without cardiovascular malformations. Of these, 15 patients (36%) underwent cardiac surgery, 24 patients (57%) showed an anatomic spleen abnormality, and seven patients (17%) showed both. The remaining 355 participants did not have SA, including 152 with SIT and 203 with SS. Overall, 70 participants (17%) harbored the severe CCDC39 or CCDC40 genotype. Compared with participants without SA, those with SA showed lower median BMI z scores (P = .03), lower FVC z scores (P = .01), and more hospitalizations and IV antibiotic courses for acute respiratory infections during the 5 years before enrollment (P < .01). Participants with cardiovascular malformations requiring surgery or with anatomic spleen abnormalities showed lower median BMI z scores and more hospitalizations and IV therapies for respiratory illnesses compared with participants without SA. INTERPRETATION: Children with PCD and SA achieve worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with SS or SIT combined. Poor nutrition and increased hospitalizations for respiratory infections in participants with SA and PCD are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both. TRIAL REGISTRY: ClinicalTrials.gov; Nos.: NCT02389049 and NCT00323167; URL: www. CLINICALTRIALS: gov.

Granulomatosis with polyangiitis in an adolescent male with chronic cough and pulmonary nodules.

Granulomatosis with polyangiitis (GPA) is a small to medium vessel vasculitis that is uncommon in paediatrics. However, with chronic cough often being the initial symptom, a common complaint and a median age of diagnosis of 14 years, it is nevertheless an important condition for paediatricians to consider as it can otherwise go undiagnosed for a long period of time. In this case report, we discuss a paediatric patient with GPA that presented with non-specific respiratory symptoms for several months and was then found to have pulmonary nodules on chest imaging once a broader differential diagnosis was considered. We will review the common presentation of GPA, the classification criteria and its management. This will ultimately assist any providers in identifying and managing GPA cases.

Going beyond the chest X-ray: Investigating laterality defects in primary ciliary dyskinesia.

BACKGROUND: Organ laterality defects in primary ciliary dyskinesia (PCD) are common, ranging from complete mirror image organ arrangement, situs inversus totalis (SIT), to situs ambiguus (SA), which falls along the spectrum of situs solitus (SS) and SIT. Targeted investigations for organ laterality defects are not universally recommended in PCD consensus statements. Without investigations beyond chest radiography (CXR), clinically significant defects may go undetected leading to increased morbidity. We hypothesize that clinically significant SA defects remain undetected on CXR and targeted investigations are needed to detect various laterality defects associated with morbidity. METHODS: This retrospective study collected data from PCD clinics at two Canadian children's hospitals from 2012 to 2020. Participants <30 years old with a confirmed or clinical diagnosis of PCD were enrolled. CXR images were reviewed, and reports of other targeted investigations, including chest computed tomography, abdominal ultrasound, echocardiogram, upper gastrointestinal series, and splenic function studies, were extracted from medical records. Situs classifications from CXR alone versus CXR with add-on targeted investigations were compared using Cochran's q and McNemar tests. RESULTS: One hundred and fifty-nine PCD patients were included, median age at PCD diagnosis of 6.1 years (range: 0-28). The situs classification differed significantly from CXR images alone versus CXR with add-on targeted investigations (p < 0.001); SS 88 (55%) versus 75 (47%), SIT 59 (37%) versus 46 (29%), and SA 12 (8%) versus 38 (24%). Identified SA defects were cardiovascular (21, 13%), intestinal (9, 6%), and/or splenic (16,10%). CONCLUSIONS: In PCD patients, clinically significant SA defects may not be detected by CXR alone. Our results suggest that the routine use of CXR with add-on targeted investigations may be justified.

Association of Neonatal Hospital Length of Stay with Lung Function in Primary Ciliary Dyskinesia.

Rationale: Primary ciliary dyskinesia (PCD), an inherited lung disease, is characterized by abnormal ciliary function leading to progressive bronchiectasis. There is wide variability in respiratory disease severity at birth and later in life. Objectives: To evaluate the association between neonatal hospital length of stay (neonatal-LOS) and supplemental oxygen duration (SuppO2) with lung function in pediatric PCD. We hypothesized that longer neonatal-LOS and SuppO2 are associated with worse lung function (i.e., forced expiratory volume in 1 second percent predicted [FEV1pp]). Methods: We performed a secondary analysis of the Genetic Disorders of Mucociliary Clearance Consortium prospective longitudinal multicenter cohort study. Participants enrolled, during 2006-2011, were <19 years old with a confirmed PCD diagnosis and followed annually for 5 years. The exposure variables were neonatal-LOS and SuppO2, counted in days since birth. The outcome, FEV1pp, was measured annually by spirometry. The associations of neonatal-LOS and SuppO2 with FEV1pp were evaluated with a linear mixed-effects model with repeated measures and random intercepts, adjusted for age and ciliary ultrastructural defects. Results: Included were 123 participants (male, 47%; mean enrollment age, 8.3 yr [range, 0 to 18 yr]) with 578 visits (median follow-up, 5 yr). The median neonatal-LOS was 9 d (range, 1 to 90 d), and median SuppO2 was 5 d (range, 0 to 180 d). Neonatal-LOS was associated with worse lung function (-0.27 FEV1pp/d [95% confidence interval, -0.53 to -0.01]; P = 0.04). SuppO2 was not associated with lung function. Conclusions: Neonatal-LOS is associated with worse lung function in pediatric PCD, independent of age and ultrastructural defects. Future research on the mechanisms of neonatal respiratory distress and its management may help us understand the variability of lung health outcomes in PCD.

Dry Powder Inhaler Delivery of Tobramycin in In Vitro Models of Tracheostomized Children.

BACKGROUND: Pediatric tracheostomies are not uncommon and aerosols allow for targeted lung therapy. However, there is little literature that quantifies aerosol delivery through tracheostomies. Nebulizers are commonly used in delivering tobramycin, but there are drawbacks, for example, time burden. Dry powder inhalers (DPIs) can deliver higher payloads in less time. However, no data exist assessing DPIs with tracheostomies. OBJECTIVE: The study's aim was to quantify the amount of aerosolized tobramycin delivered to the lungs of in vitro tracheostomized spontaneously breathing pediatric models with the TOBI® Podhaler™ (Podhaler) and the PARI LC Plus® (LC Plus). METHODS: In vitro tracheostomized models of a 6- and 12-year-old trachea were created. Tobramycin aerosol was delivered to the models using either the LC Plus or Podhaler and captured on a filter at the trachea's distal end. A colorimetric tobramycin assay was used to quantify the amount. Three devices of each type were tested in triplicate to ensure repeatability. RESULTS: A total of 36 runs were completed and showed that the Podhaler was more efficient compared with the LC Plus. Mass and percentage of nominal dose, mean ± standard deviation (LC Plus vs. Podhaler with single capsule), was 72.4 ± 11.1 mg (24.1% ± 3.7%) versus 24.2 ± 2.4 mg (86.6% ± 8.7%); p < 0.001. CONCLUSIONS: The study's results show that the Podhaler was significantly more efficient compared with the LC Plus, and three Podhaler capsules delivered approximately the same amount of drug as the Tobramycin inhalation solution. These results suggest that Podhaler's tobramycin delivery is a feasible option in tracheostomized pediatric patients and a clinical study is warranted.

Recurrent Diplopia in a Pediatric Patient with Bickerstaff Brainstem Encephalitis.

Introduction. Acute complete external ophthalmoplegia is a rare finding in clinical practice that is associated with diseases affecting the neuromuscular junction, the oculomotor nerves, or the brainstem. Ophthalmoplegia has been reported with acute ataxia in Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE). Up to 95% of these cases are associated with anti-GQ1b antibodies. Only a small number of cases of anti-GQ1b negative MFS have been documented in pediatric patients. This is the first case reporting a recurrence of ocular symptoms in an anti-GQ1b antibody negative patient with BBE. Case Presentation. An 8-year-old Caucasian boy presented with complete external ophthalmoplegia without ptosis, cerebellar ataxia, and a disturbance of consciousness. He had recently recovered from a confirmed Campylobacter jejuni infection. On subsequent laboratory testing he was anti-GQ1b antibody negative. He had a recurrence of diplopia at four-week follow-up. Conclusions. This patient's recurrence of diplopia was treated with a five-week course of oral corticosteroids which did not worsen his condition, and this may be a therapeutic option for similar patients. We will discuss the symptoms and treatment of reported pediatric cases of anti-GQ1b antibody negative cases of MFS and the variation between cases representing a spectrum of illness.

Modeling breath-enhanced jet nebulizers to estimate pulmonary drug deposition.

BACKGROUND: Predictable delivery of aerosol medication for a given patient and drug-device combination is crucial, both for therapeutic effect and to avoid toxicity. The gold standard for measuring pulmonary drug deposition (PDD) is gamma scintigraphy. However, these techniques expose patients to radiation, are complicated, and are relevant for only one patient and drug-device combination, making them less available. Alternatively, in vitro experiments have been used as a surrogate to estimate in vivo performance, but this is time-consuming and has few "in vitro to in vivo" correlations for therapeutics delivered by inhalation. An alternative method for determining inhaled mass and PDD is proposed by deriving and validating a mathematical model, for the individual breathing patterns of normal subjects and drug-device operating parameters. This model was evaluated for patients with cystic fibrosis (CF). METHODS: This study is comprised of three stages: mathematical model derivation, in vitro testing, and in vivo validation. The model was derived from an idealized patient's respiration cycle and the steady-state operating characteristics of a drug-device combination. The model was tested under in vitro dynamic conditions that varied tidal volume, inspiration-to-expiration time, and breaths per minute. This approach was then extended to incorporate additional physiological parameters (dead space, aerodynamic particle size distribution) and validated against in vivo nuclear medicine data in predicting PDD in both normal subjects and those with CF. RESULTS: The model shows strong agreement with in vitro testing. In vivo testing with normal subjects yielded good agreement, but less agreement for patients with chronic obstructive lung disease and bronchiectasis from CF. CONCLUSIONS: The mathematical model was successful in accommodating a wide range of breathing patterns and drug-device combinations. Furthermore, the model has demonstrated its effectiveness in predicting the amount of aerosol delivered to "normal" subjects. However, challenges remain in predicting deposition in obstructive lung disease.