Maternal and Fetal Outcomes in Multiparous Women with Cystic Fibrosis.

BACKGROUND: Quality of life and survival in Cystic Fibrosis (CF) have improved dramatically, making family planning a feasible option. Maternal and perinatal outcomes in women with CF (wwCF) are similar to those seen in the general population. However, the effect of undergoing multiple pregnancies is unknown. METHODS: A multinational-multicenter retrospective cohort study. Data was obtained from 18 centers worldwide, anonymously, on wwCF 18-45 years old, including isease severity and outcome, as well as obstetric and newborn complications. Data was analyzed, within each individual patient to compare the outcomes of an initial pregnancy (1st or 2nd) with a multigravid pregnancy (≥3) as well as secondary analysis of grouped data to identify risk factors for disease progression or adverse neonatal outcomes. Three time periods were assessed - before, during, and after pregnancy. RESULTS: The study population included 141 wwCF of whom 41 (29%) had ≥3 pregnancies, "multiparous". Data was collected on 246 pregnancies, between 1973 and 2020, 69 (28%) were multiparous. A greater decline in ppFEV1 was seen with multiparous women, primarily in pancreatic insufficient (PI) wwCF and those with two severe (class I-III) mutations. Multigravid pregnancies were shorter, especially in wwCF over 30 years old, who had high rates of prematurity and newborn complications. There was no effect on pulmonary exacerbations or disease-related complications. CONCLUSIONS: Multiple pregnancies in wwCF are associated with accelerated respiratory deterioration and higher rates of preterm births. Therefore, strict follow-up by a multidisciplinary CF and obstetric team is needed in women who desire to carry multiple pregnancies.

Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study.

BACKGROUND: The prevalence of nontuberculous mycobacteria (NTM) infections is rising in people with cystic fibrosis (pwCF). NTM infection, especially infection with Mycobacterium abscessus complex (MABC), is commonly associated with severe lung deterioration. The current treatment modalities, including multiple intravenous antibiotics, frequently fail to achieve airway eradication. Although treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to modulate the lung microbiome, data regarding its role in eradicating NTM in pwCF is lacking. Our aim was to evaluate the impact of ETI on the rate of NTM eradication in pwCF. METHODS: This retrospective multicenter cohort study included pwCF from five CF centers in Israel. PwCF aged older than 6 who had at least one positive NTM airway culture in the past two years and were treated with ETI for at least one year were included. The annual NTM and bacterial isolations, pulmonary function tests, and body mass index were analyzed before and after ETI treatment. RESULTS: Fifteen pwCF were included (median age 20.9 years, 73.3% females, 80% pancreatic insufficient). In nine patients (66%) NTM isolations were eradicated following treatment with ETI. Seven of them had MABC. The median time between the first NTM isolation and treatment with ETI was 2.71 years (0.27-10.35 years). Eradication of NTM was associated with improved pulmonary function tests (p<0.05). CONCLUSIONS: For the first time, we report successful eradication of NTM, including MABC, following treatment with ETI in pwCF. Additional studies are needed to assess whether treatment with ETI can result in the long-term eradication of NTM.

Foreign body aspiration score (FOBAS)-a prospectively validated algorithm for the management and prediction of foreign body aspiration in children.

Foreign body aspiration (FBA) is a common cause of pediatric morbidity, but a standardized protocol to guide decision-making about bronchoscopy is lacking. We aimed to validate a new Foreign body aspiration score (FOBAS) for the pediatric emergency department (ED). Patients aged 0-18 years referred to the ED for suspected FBA were prospectively enrolled. FOBAS was calculated according to clinical features of a choking episode, sudden cough, exposure to nuts, absence of fever and rhinitis, stridor, and unilateral auscultatory and radiological findings. FBA risk was evaluated based on the total score (low, 1-3; moderate, 4-6; high, 7-10). Low-risk children were discharged from the ED and followed clinically. Moderate-risk children were hospitalized and evaluated by a pediatric pulmonologist, and high-risk children were referred directly for therapeutic bronchoscopy. Among the 100 enrolled children (59% males; median age 20 [interquartile range 11-39] months), a foreign body was diagnosed in 1/49 (2%), 14/41 (34.1%), and 9/10 (90%) with low, moderate, and high FOBAS, respectively (P < .001). Logistic regression indicated a higher risk for FBA with higher scores. The odds ratio for each additional point was 2.75 (95% confidence interval 1.78-4.24), and FOBAS showed a high predictive value for FBA (area under the curve 0.89). FOBAS implementation significantly reduced the rate of negative bronchoscopies, from 67.4% annually during 2016-2019 to 50% in 2020 (P = .042). CONCLUSION: FOBAS reliably predicts FBA in cases of suspected FBA and improves management and in-hospital decision-making. WHAT IS KNOWN: • Foreign body aspiration is a major cause of pediatric morbidity and mortality. • Currently, there is no unified protocol for children referred to the emergency department for suspected FBA, therefore, a well-defined algorithm is needed to improve the decision-making process. WHAT IS NEW: • The pediatric Foreign body aspiration score (FOBAS) is a new, prospectively validated clinical score that shows high sensitivity and specificity for the presence of FBA in children. • FOBAS reduces unnecessary admissions and invasive procedures and leads to better clinical outcomes.

The new face of cystic fibrosis in the era of population genetic carrier screening.

BACKGROUND: Population genetic carrier screening (PGCS) for cystic fibrosis (CF) has been offered to couples in Israel since 1999 and was included in a fully subsidized national program in 2008. We evaluated the impact of PGCS on CF incidence, genetic and clinical features. METHODS: This was a retrospective national study. Demographic and clinical characteristics of children with CF born in Israel between 2008 and 2018 were obtained from the national CF registry and from patients' medical records. Data on CF births, preimplantation genetic testing (PGT), pregnancy termination and de-identified data from the PGCS program were collected. RESULTS: CF births per 100,000 live births decreased from 8.29 in 2008 to 0.54 in 2018 (IRR = 0.84, p < 0.001). The CF pregnancy termination rate did not change (IRR = 1, p=  0.9) while the CF-related PGT rate increased markedly (IRR = 1.33, p < 0.001). One hundred and two children were born with CF between 2008 and 2018 with a median age at diagnosis of 4.8 months, range 0-111 months. Unlike the generally high uptake nationally, 65/102 had not performed PGCS. Even if all had utilized PGCS, only 51 would have been detected by the existing genetic screening panel. Clinically, 34 % of children were pancreatic sufficient compared to 23 % before 2008 (p = 0.04). CONCLUSIONS: Since institution of a nationwide PGCS program, the birth of children with CF decreased markedly. Residual function variants and pancreatic sufficiency were more common. A broader genetic screening panel and increased PGCS utilization may further decrease the birth of children with CF.

Evaluation of Foreign body aspiration score (FOBAS) in children- A retrospective cohort study.

Foreign Body Aspiration (FBA) is a common medical emergency among young children, but the evaluation and management of a suspected FBA case can vary across physicians and centers. We aimed to identify which clinical, laboratory, and radiological findings can predict FBA in children and to evaluate a clinical score to improve FBA prediction. This is a retrospective cohort study of patients aged 0-18 years admitted to Soroka University Medical Center between 2010 and 2020 with suspected FBA. All patients underwent flexible bronchoscopy and were divided into positive and negative FBA groups. A newly developed foreign body aspiration score (FOBAS), based on medical history, physical examination, and chest X-ray findings, was evaluated for its predictability. The study included 412 children (median age 21 months, 56.8% females), of whom 154 (37.4%) had FBA and 258 (62.6%) did not. Multivariate regression analysis showed exposure to nuts/seeds, unilateral wheezing or decreased breath sounds, stridor, and suggestive findings on chest X-ray were significant risk factors for FBA (OR [95%CI] -1.994[1.290-3.082], 1.487[1.206-1.832], 1.883 [1.011-3.509] and 2.386[1.917-2.970], respectively). However, a choking episode, acute cough, and absence of fever and rhinorrhea did not predict FBA. FOBAS showed an increased risk of FBA for each additional point of the score, with an odds ratio of 1.572 (95% CI-1.389-1.799).  Conclusion: FOBAS is a good predictor for the presence of FBA in children. Once prospectively validated, FOBAS could aid in decision-making at the emergency department, enabling more standardized care, reducing unnecessary procedures, and leading to better clinical outcomes. What is Known: • The evaluation and management of a child with suspected foreign body aspiration (FBA) vary across physicians and centers, without a consensus regarding the indications and criteria for performing bronchoscopy. • Flexible bronchoscopy is the standard procedure for the diagnosis and sometimes treatment of FBA in children, but it may hold potential complications. What is New: • We propose a newly developed foreign body aspiration score (FOBAS), based on medical history, physical examination, and chest X-ray findings, for the prediction of FBA in children at the emergency department. • The FOBAS is a good predictor of FBA in children. The score enables more standardized care and may reduce unnecessary procedures.

Comparison of chest X-ray interpretation by pediatric pulmonologists, pediatric radiologists, and pediatric residents in children with suspected foreign body aspiration-a retrospective cohort study.

Chest X-ray (CXR) is an important tool in the assessment of children with suspected foreign body aspiration (FBA), although it can falsely be interpreted as normal in one-third of the cases. The aim of this study is to evaluate the positive predictive value of CXR in children hospitalized with suspected FBA, when interpreted by three disciplines: pediatric pulmonology, pediatric radiology, and pediatric residents. This is a retrospective study that included children aged 0-18 years, admitted with suspected FBA, between 2009 and 2020 in one tertiary center. All patients underwent CXR and a flexible/rigid bronchoscopy for the definitive diagnosis of FBA, up to 1 week apart. Two physicians from each discipline interpreted the CXR, independently. Intra-raters' and inter-raters' agreements were assessed. Sensitivity, specificity, and area under the curve (AUC) were calculated for each discipline. Four hundred seventy-three children were included in the study, 175 (37%) with FBA and 298 (63%) without FBA on flexible/rigid bronchoscopy. The most common radiological findings, as interpreted by a pediatric pulmonologist, were unilateral hyperinflation (47%), radiopaque FB (37.6%), lobar atelectasis (10.3%), unilateral hyperinflation with atelectasis (3.4%), and lobar consolidation (1.7%). Intra-raters' agreement ranged from 0.744 (p < 0.001) among pediatric pulmonologists to 0.326 (p < 0.001) among pediatric radiologists. AUC for predicting FBA based on a CXR was 0.81, 0.77, and 0.7 when interpreted by pediatric pulmonologists, pediatric residents, and radiologists, respectively (p < 0.001). CONCLUSIONS: CXR has a high positive predictive value and independently predicts FBA in children; however, normal CXR should not rule out FBA. Predictability is variable among different disciplines. WHAT IS KNOWN: • Chest X-ray is an important tool in the assessment of children with suspected foreign body aspiration (FBA). • Chest X-ray can be interpreted as normal in one-third of the cases. WHAT IS NEW: • Chest X-ray independently predicts FBA in children, with a high positive predictive value. • The ability of chest x-ray to predict FBA in children differs between pediatric residents, pediatric radiologists, and pediatric pulmonologists.

Flexible bronchoscopy in pediatric patients with Down syndrome: A case-control study of the indications, findings, and complications.

BACKGROUND: Children with Down syndrome (DS) often undergo flexible bronchoscopies (FB) due to common respiratory symptoms. OBJECTIVE: To examine the indications, findings, and complications of FB in pediatric DS patients. METHODS: A retrospective case-control study on FB performed in DS pediatric patients between 2004 and 2021 in a tertiary center. DS patients were matched to controls (1:3) based on age, gender, and ethnicity. Data collected included demographics, comorbidities, indications, findings, and complications. RESULTS: Fifty DS patients (median age 1.36 years, 56% males) and 150 controls (median age 1.27 years, 56% males), were included. Evaluation for obstructive sleep apnea and oxygen dependence were more common indications among DS (38% vs. 8%, 22% vs. 4%, p < 0.01, respectively). Normal bronchoscopy was less frequent in DS compared with controls (8% vs. 28%, p = 0.01). Soft palate incompetence and tracheal bronchus were more frequent in DS (12% vs. 3.3%, p = 0.024, 8% vs. 0.7%, p = 0.02, respectively). Complications were more frequent in DS (22% vs. 9.3%, incidence rate ratio [IRR] 2.36, p = 0.028). In DS, cardiac anomalies (IRR 3.96, p < 0.01), pulmonary hypertension (IRR 3.76, p = 0.006), and pediatric intensive care unit (PICU) hospitalization before the procedure (IRR 4.2, p < 0.001) were associated with higher complication rates. In a multivariate regression model, history of cardiac disease and PICU hospitalization before the procedure, but not DS, were independent risk factors for complications with an IRR of 4 and 3.1, respectively (p = 0.006, p = 0.05). CONCLUSION: DS pediatric patients undergoing FB are a unique population with specific indications and findings. DS pediatric patients with cardiac anomalies and pulmonary hypertension are at the highest risk for complications.

Foreign body aspiration in Israeli children during the COVID-19 pandemic.

BACKGROUND: Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, there has been a decline in pediatric emergency department visits. Our aim was to assess the pattern of pediatric foreign body aspiration (FBA) during the first year of the COVID-19 pandemic, in comparison to the prior years. METHODS: In this retrospective multicenter study, we compared the number of children who presented with FBA during the COVID-19 year (March 1, 2020 to February 28, 2021) to the annual average of the years 2016-2019. We also compared the lockdown periods to the postlockdown periods, and the percentage of missed FBA, proven FBA, and flexible bronchoscopy as the removal procedure. RESULTS: A total of 345 children with FBA from six centers were included, 276 in the pre-COVID-19 years (average 69 per year) and 69 in the COVID-19 year. There was no difference in the prevalence of FBA between the COVID-19 year and any of the prior 4 years. Examining the lockdown effect, the monthly incidence of FBA dropped from a pre-COVID-19 average of 5.75 cases to 5.1 cases during lockdown periods and increased to 6.3 cases in postlockdown periods. No difference in the percentage of missed FB or proven FB was observed. There was a significant rise in the usage of flexible bronchoscopy as the removal procedure (average of 15.4% vs. 30.4%, p = 0.001). CONCLUSION: There were fewer cases of pediatric FBA during lockdown periods, compared to post-lockdown periods, presumably related to better parental supervision, with no difference in the prevalence of FBA during the COVID-19 year.

From rigid to flexible bronchoscopy: a tertiary center experience in removal of inhaled foreign bodies in children.

Rigid bronchoscopy is the procedure of choice for removal of inhaled foreign bodies. In this retrospective study, we assessed the safety and efficacy of flexible bronchoscopy use in the removal of inhaled foreign bodies in children. One hundred eighty-two patients (median age of 24 months, 58% males) underwent an interventional bronchoscopy for the removal of inhaled foreign body between 2009 and 2019, 40 (22%) by flexible, and 142 (78%) by rigid bronchoscopy. 88.73% of rigid and 95% of flexible bronchoscopies were successful in foreign bodies removal (p value = 0.24). Complication rate was higher among rigid bronchoscopy (9.2% vs. 0%, p = 0.047). From 2017 onwards, following the implementation of flexible bronchoscopy for foreign bodies removal, 64 procedures were performed, 33 (51.6%) flexible, and 31 (48.4%) rigid. Procedure length was shorter via flexible bronchoscopy (42 vs 58 min, p = 0.016). Length of hospital stay was similar.Conclusion: In our hands, flexible bronchoscopy is an efficient and safe method for removal of inhaled foreign bodies in children, with shorter procedure time and minimal complication rate. Flexible bronchoscopy could be considered as the procedure of choice for removal of inhaled foreign bodies in children, by an experienced multidisciplinary team. What is Known: • Rigid bronchoscopy is currently the gold standard for removal of inhaled foreign bodies in children. • Rigid bronchoscopy has a relatively high complication rate compared to flexible bronchoscopy. What is New: • Flexible bronchoscopy is a short, safe, and efficient procedure to remove inhaled foreign bodies in children, compared to rigid bronchoscopy. • Flexible bronchoscopy could be proposed as the procedure of choice for removal of inhaled foreign bodies in children, if an experienced operator is available.

Baseline Cystic fibrosis disease severity has an adverse impact on pregnancy and infant outcomes, but does not impact disease progression.

BACKGROUND: With increasing longevity and quality of life in adults with Cystic fibrosis (CF), growing maternity rates are reported. Women with severe CF are becoming pregnant, with unpredictable maternal and fetal outcomes. AIM: To determine how baseline disease severity, pancreatic insufficiency (PI) and Pseudomonas aeruginosa (PA) infection affect fertility, the pregnancy course, delivery, neonatal outcome, and subsequent disease progression. METHODS: A multicenter-retrospective cohort study. Data on patients that had been pregnant between 1986-2018 was collected from ten CF centers worldwide. Disease severity [mild or moderate-severe (mod-sev)] was defined according to forced expiratory volume % predicted in 1 second (FEV1) and body mass index (BMI). Three time periods were compared, 12 months prior to conception, the pregnancy itself and the 12 months thereafter. RESULTS: Data was available on 171 pregnancies in 128 patients aged 18-45 years; 55.1% with mod-sev disease, 43.1% with PI and 40.3% with PA. Women with mod-sev disease had more CF-related complications during and after pregnancy and delivered more preterm newborns. However, FEV1 and BMI decline were no different between the mild and mod-sev groups. A more rapid decline in FEV1 was observed during pregnancy in PI and PA infected patients, though stabilizing thereafter. PI was associated with increased risk for small for gestational age infants. CONCLUSION: Baseline disease severity, PA infection and PI have an adverse impact on infant outcomes, but do not impact significantly on disease progression during and after pregnancy. Consequently, pregnancies in severe CF patients can have a good prognosis.

A 9-Year-Old Boy With Recurrent Chest Pain and Nonresolving Pneumonia.

CASE PRESENTATION: A previously healthy, 9-year-old boy presented with five recurrent episodes of left-sided chest pain with low-grade fever over the last 18 months. The pain usually lasted for few hours, was severe and consistent, and resolved spontaneously. It worsened during inspiration, physical activity, and swallowing. He did not experience any cough, dyspnea, chills, cold sweats, or weight loss. His medical and family history was unremarkable.

CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module.

Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45-/- mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module.

Pilot study to test inhaled nitric oxide in cystic fibrosis patients with refractory Mycobacterium abscessus lung infection.

BACKGROUND: Airways of Cystic Fibrosis (CF) patients are Nitric Oxide (NO) deficient which may contribute to impaired lung function and infection clearance. Mycobacterium abscessus (M. abscessus) infection prevalence is increasing in CF patients and is associated with increased morbidity and mortality. Here, we assess the safety and efficacy of intermittent inhaled NO (iNO) as adjuvant therapy in CF patients with refractory M. abscessus lung infection. METHODS: A prospective, open-label pilot study of iNO (160 ppm) administered five times/day during hospitalization (14 days), and three times/day during ambulatory treatment (7 days) was conducted. The primary outcome was safety measured by NO-related adverse events (AEs). Secondary outcomes were six-minute walk distance (6MWD), forced expiratory volume in 1 s (FEV1), and M. abscessus burden in airways. RESULTS: Nine subjects were recruited. INO at 160 ppm was well-tolerated and no iNO-related SAEs were observed during the study. Mean FEV1 and 6WMD were increased relative to baseline during NO treatment. M. abscessus culture conversion was not achieved, but 3/9 patients experienced at least one negative culture during the study. Mean time to positivity in M. abscessus culture, and qPCR analysis showed reductions in sputum bacterial load. The study was not powered to achieve statistical significance in FEV1, 6WMD, and bacterial load. CONCLUSIONS: Intermittent iNO at 160 ppm is well tolerated and safe and led to increases in mean 6MWD and FEV1. INO exhibited potential antibacterial activity against M. abscessus. Further evaluation of secondary endpoints in a larger cohort of CF patients is warranted to demonstrate statistical significance.

Failure to conceive in women with CF is associated with pancreatic insufficiency and advancing age.

OBJECTIVE: The causes of subfertility in women with CF though multifactorial are not well described. Our aim in this study was to determine the prevalence and factors associated with female subfertility among women with CF. METHODS: A retrospective multinational study from 11 CF centers in 5 countries (Israel, France, Spain, Italy, UK) including women with CF was undertaken. Sub/infertility was defined as not achieving a spontaneous pregnancy after one year of unprotected sexual intercourse. Data including genetics, pancreatic insufficiency (PI), prevalence of diabetes (CFRD), lung function, nutritional status measured by body mass index (BMI), sputum bacterial colonization, and rate of pulmonary exacerbations were collected from patients' files. RESULTS: Out of 605 women, 241 attempted pregnancy. Of these, 84 (35%) had subfertility, and 67 of them eventually became pregnant. Females attempting conception were older but had better pulmonary function and nutrition compared to those who did not. In a multivariate analysis, PI (OR 1.9 [1.03-3.5], p = .04) and older age (OR 3.9 [2.1-7.3] p < .0001) were associated with subfertility. Lung function, BMI, CFRD, Presence of two class I-III mutations and number of exacerbations in the year prior to fertility attempts were not associated with subfertility. CONCLUSIONS: The prevalence of subfertility among women with CF (35%) is higher than the expected 5-15% subfertility in the general population. Older age and pancreatic insufficiency are associated with subfertility in women with CF.

Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening.

BACKGROUND: Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. METHODS: An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts. RESULTS: We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel. CONCLUSIONS: Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis.

Eradication of Pseudomonas aeruginosa (PA) is critical in cystic fibrosis (CF) patients. OBJECTIVES: To determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure. METHODS: In an observational study, data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for ≥1year. RESULTS: Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultures taken, were older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken. CONCLUSIONS: Delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure.

DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes.

Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-of-function DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed high-resolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-left-right dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.

The impact of a national population carrier screening program on cystic fibrosis birth rate and age at diagnosis: Implications for newborn screening.

BACKGROUND: Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. METHODS: A retrospective review of governmental databanks, the national CF registry and CF centers. RESULTS: CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. CONCLUSIONS: PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening.

Evaluation of the intestinal current measurement method as a diagnostic test for cystic fibrosis.

BACKGROUND: The sweat test and nasal potential difference measurement are now established tools in the diagnostic work up of cystic fibrosis (CF). Intestinal current measurement (ICM) is under consideration as an aid in the diagnosis of CF especially in young children. The aim of this study is to evaluate the diagnostic reliability of ICM. METHODS: Rectal biopsies were obtained from three groups: CF patients, controls, and patients who were suspected for CF. ICMs were performed by mounting the rectal biopsy in an Ussing chamber and sequentially adding secretagogues while recording current changes. RESULTS: Twenty-one CF patients (aged 3.0 ± 3.8 years) and 16 controls (aged 15.6 ± 15.1 years) were examined and have remarkably different results (presented as µA/cm(2) ): carbachol 16.3 ± 6.9, histamine 13.2 ± 8.9, and cAMP/forskolin 4.8 ± 4.0 for control group and carbachol -1.5 ± 5.3 (P < 0.0001), histamine -1.5 ± 3.1 (P < 0.0001), and cAMP/forskolin 0.36 ± 0.67 (P < 0.0001) for the CF group. Our suggested reference values are: +5.40, +3.52, +2.19 for carbachol, histamine, and cAMP/forskolin, respectively. The combination parameter (the arithmetic sum of carbachol, histamine, and cAMP/forskolin) of +7.19 differentiates normal from abnormal (ROC curve analysis, area under the curve = 1.00, both sensitivity and specificity are 100%). This statistical model was applied to 71 patients suspected for CF and revealed that 66 patients had normal ICM results (combination >7.19) and five patients had abnormal ICM results (combination <7.19). CONCLUSION: We have shown that ICM tests may be useful to differentiate between patients suspected to have CF. These results require confirmation so that ICM may be included in diagnostic algorithms.