Cerebrocostomandibular syndrome: a diagnostic challenge.

A male infant born in a tertiary maternity facility was noted to have microretrognathia, a small mouth and macroglossia at delivery. He was born limp and apnoeic and required multiple attempts at intubation before a definitive airway was eventually sited. Chest X-rays, while in the paediatric intensive care unit, demonstrated dysplastic ribs with associated 'high-riding' clavicles. A later X-ray was reported as showing interrupted posterior ribs. A tracheostomy was formed on day of life 9 given the immediate risk to the baby's airway. Further imaging of the facial bones, skull and brain showed generous CSF spaces over the cerebral convexities and also marked hypoplasia of the mandible and mid-face. The baby's middle ear cavities were shown to be completely opacified. Genetic testing eventually went on to confirm a diagnosis of cerebrocostomandibular syndrome, with the detection of a pathogenic variant of the small nuclear ribonucleoprotein polypeptide B gene.

Contributions from functional neuroimaging studies to the comprehension of traumatic child experiences: preliminary findings / Aportes de los estudios de neuroimagen funcional a la comprensión del trauma infantil: estudio preliminar

Abstract This study aimed to describe the cerebral activation patterns using fMRI (Functional Magnetic Resonance Imaging) technology in a sample of 15 children with Posttraumatic Stress Disorder (PTSD) and 7 with no PTSD. The study used a Quasi-experimental methodology where two experimental tasks were applied: an emotional face task and a version of an emotional Stroop task. The results point out differences in the group of PTSD on the processing of negative stimuli and changes in their frontal lobe activation. These preliminary results suggest that early traumatic experiences affect typical brain development patterns. And explicit and implicit variables involved in the traumatic experiences are discussed as a part of any intervention process.

Resumen El presente estudio tuvo como objetivo describir patrones de activación cerebral mediante una técnica de Imagen por resonancia magnética funcional -fMRI- (abreviatura en inglés de Functional Magnetic Resonance Imaging) en una muestra de niños con Trastorno de estrés postraumático (TEPT) y compararlos con un grupo de controles. Estudio cuasi-experimental en el que se tomó un grupo de 15 niños con TEPT y se comparó con un grupo de 7 niños sin TEPT. Se emplearon dos tareas experimentales: una prueba de caras y una versión del Stroop emocional. Los resultados preliminares, señalan diferencias en el procesamiento de estímulos, principalmente de carácter negativo en los niños con TEPT y cambios en los patrones de activación a nivel de estructuras frontales. Se concluye que el trauma a edad temprana afecta el curso normal del desarrollo cerebral y se evidencia la importancia de abordar los aspectos explícitos e implícitos asociados a la experiencia traumática como parte de la intervención.

Experience of low-dose dexamethasone use in the respiratory management of ichthyosis prematurity syndrome.

Ichthyosis prematurity syndrome (IPS) is a rare disorder of autosomal recessive inheritance. The cardinal features include prematurity, vernix like hyperkeratosis, eosinophilia and neonatal asphyxiation. This case report discusses the presentation and management of IPS. We aim to characterise the common features, the spectrum of disease within a single family and discuss a potential role for low-dose dexamethasone in the management of ventilator-dependent patients with IPS.

Neonatal thyroid storm: the importance of an accurate antenatal history.

A near-term infant became unwell immediately after birth with cardiorespiratory compromise-persistent tachycardia, pulmonary hypertension and reduced cardiac function. There had been no concerns during the pregnancy and the obstetrical and maternal medical history was unremarkable apart from hypothyroidism. A thyroid function test on admission revealed a significantly elevated free T4 and a diagnosis of a thyroid storm was made. On questioning it became apparent that she had Graves' disease after her last pregnancy and was rendered hypothyroid post surgery, she was not aware of the relevance of this at her booking visit. This case highlights the importance of monitoring of women who have a history of a diagnosis of Graves' disease, regardless of thyroid function status, to allow for appropriate antenatal monitoring, preparedness of the NICU (neonatal intensive care unit) team and correct follow-up of the neonate. It also demonstrates the importance of ensuring a patient is properly educated about their condition.

Nurse home visiting and prenatal substance use in a socioeconomically disadvantaged population in British Columbia: analysis of prenatal secondary outcomes in an ongoing randomized controlled trial.

BACKGROUND: Nurse-Family Partnership (NFP) involves public health nurses providing frequent home visits from early pregnancy until children reach age 2 years, focusing on first-time parents experiencing socioeconomic disadvantage. Our aim was to evaluate NFP's effectiveness in improving child and maternal health. METHODS: We conducted an analysis of prenatal secondary outcomes in an ongoing randomized controlled trial in British Columbia; the data used in this analysis were collected from January 2014 to May 2017. Participants were pregnant girls and women aged 14-24 years who were preparing to parent for the first time and experiencing socioeconomic disadvantage. They were randomly allocated 1:1 to the intervention (NFP plus existing services) or control group (existing services). Prespecified prenatal secondary outcome indicators were changes in use of nicotine cigarettes and alcohol use by 34-36-weeks' gestation. We also report on prespecified exploratory cannabis and street drug use measures. We used mixed-effect models for longitudinal and clustered data to estimate intervention effects. Analyses were by intention to treat. RESULTS: The median gestational age at baseline for the 739 participants (368 participants in the intervention group, 371 in the comparison group) was 20 weeks, 6 days. By 34-36 weeks' gestation, NFP significantly reduced cigarette counts (over the past 2 d) (difference in changes [DIC] of count -1.6, 95% confidence interval [CI] -6.4 to -1.3) in those who smoked. NFP also significantly reduced rates of prenatal cannabis use (DIC -6.4, 95% CI -17.0 to -1.7), but not rates of street drug or "any" substance use. While we observed decreased rates of cigarette and alcohol use in both groups (DIC of proportions -2.8, 95% CI -15.3 to 0.6; DIC -0.5, 95% CI -8.7 to 1.8, respectively), these changes were not statistically significant. INTERPRETATION: We found no evidence that NFP was effective in reducing rates of prenatal cigarette and alcohol use; however, it led to reduced prenatal cannabis use, and in smokers it led to modest reductions in cigarette use. NFP may therefore hold promise for reducing some types of prenatal substance use in disadvantaged populations. Trial registration: ClinicalTrials.gov, no. NCT01672060.

Infectious Complications of Biological and Small Molecule Targeted Immunomodulatory Therapies.

The past 2 decades have seen a revolution in our approach to therapeutic immunosuppression. We have moved from relying on broadly active traditional medications, such as prednisolone or methotrexate, toward more specific agents that often target a single receptor, cytokine, or cell type, using monoclonal antibodies, fusion proteins, or targeted small molecules. This change has transformed the treatment of many conditions, including rheumatoid arthritis, cancers, asthma, and inflammatory bowel disease, but along with the benefits have come risks. Contrary to the hope that these more specific agents would have minimal and predictable infectious sequelae, infectious complications have emerged as a major stumbling block for many of these agents. Furthermore, the growing number and complexity of available biologic agents makes it difficult for clinicians to maintain current knowledge, and most review articles focus on a particular target disease or class of agent. In this article, we review the current state of knowledge about infectious complications of biologic and small molecule immunomodulatory agents, aiming to create a single resource relevant to a broad range of clinicians and researchers. For each of 19 classes of agent, we discuss the mechanism of action, the risk and types of infectious complications, and recommendations for prevention of infection.

Characterization of a Novel FLT3 BiTE Molecule for the Treatment of Acute Myeloid Leukemia.

Despite advances in the treatment of acute myeloid leukemia (AML), novel therapies are needed to induce deeper and more durable clinical response. Bispecific T-cell Engager (BiTE) molecules, which redirect patient T cells to lyse tumor cells, are a clinically validated modality for hematologic malignancies. Due to broad AML expression and limited normal tissue expression, fms-related tyrosine kinase 3 (FLT3) is proposed to be an optimal BiTE molecule target. Expression profiling of FLT3 was performed in primary AML patient samples and normal hematopoietic cells and nonhematopoietic tissues. Two novel FLT3 BiTE molecules, one with a half-life extending (HLE) Fc moiety and one without, were assessed for T-cell-dependent cellular cytotoxicity (TDCC) of FLT3-positive cell lines in vitro, in vivo, and ex vivo FLT3 protein was detected on the surface of most primary AML bulk and leukemic stem cells but only a fraction of normal hematopoietic stem and progenitor cells. FLT3 protein detected in nonhematopoietic cells was cytoplasmic. FLT3 BiTE molecules induced TDCC of FLT3-positive cells in vitro, reduced tumor growth and increased survival in AML mouse models in vivo Both molecules exhibited reproducible pharmacokinetic and pharmacodynamic profiles in cynomolgus monkeys in vivo, including elimination of FLT3-positive cells in blood and bone marrow. In ex vivo cultures of primary AML samples, patient T cells induced TDCC of FLT3-positive target cells. Combination with PD-1 blockade increased BiTE activity. These data support the clinical development of an FLT3 targeting BiTE molecule for the treatment of AML.

Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia.

Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia (AML). AMG 553 is an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of AML. FLT3 expression analysis and in vitro and in vivo studies were leveraged to evaluate the nonclinical safety of AMG 553. Cynomolgus monkeys administered autologous anti-FLT3 CAR T cells demonstrated no evidence of CAR T-cell-mediated toxicity, expansion, or persistence, likely due to restricted cell surface FLT3 protein expression in healthy animals. This highlights the limited value of such in vivo studies for safety assessment of the CAR T-cell modality when directed against a target with restricted expression. To complement these studies and directly evaluate the potential toxicities of eliciting T-cell-mediated cytotoxicity against cells with surface expression of FLT3 protein in vivo, data from cynomolgus monkey toxicology studies with 2 bispecific T-cell engager molecules targeting FLT3 were leveraged; findings were consistent with the targeted killing of bone marrow cells expressing cell surface FLT3. Potential AMG 553-induced cytotoxicity was assessed against a wide range of normal human primary cells and cell lines; cytotoxicity was observed against FLT3-positive AML cell lines and a percentage of primary bone marrow CD34+ cells. In conclusion, the nonclinical safety data suggest that AMG 553 can target FLT3 protein on AML cells, whereas only affecting a percentage of normal hematopoietic stem and progenitor cells, supporting clinical development.

Integrative Review of Dietary Choice Revealed by fMRI: Considerations for Obesity Prevention and Weight-Loss Education.

BACKGROUND: Emerging findings from neuroimaging studies investigating brain activity associated with dietary behavior are illuminating the interaction of biological and behavioral mechanisms that have implications for obesity prevention. Globally, A total of 1.9 billion adults are overweight, and 650 million are obese. Obesity and being overweight are major risk factors for chronic illness and death. Behaviorally based health interventions have had limited success in curbing the obesity epidemic. Greater understanding of brain responses to food cues will contribute to new knowledge and shape public health efforts in obesity prevention. However, an integration of this knowledge for obesity prevention education has not been published. AIMS: This study links evidence generated from brain activation studies generated in response to diet and food images and highlights educational recommendations for nurses engaged in obesity prevention and weight-loss education. METHODS: An integrative review of the literature was conducted using the MeSH keywords "magnetic resonance imaging," "diet," and "food images" in PubMed, MEDLINE Complete, CINAHL, and Cochrane databases from their first appearance in 2006 through March 2018. Studies published in English and using functional magnetic resonance imaging to measure brain response to diet, and food images were initially identified. Animal models, those whose primary focus was a specific disease, and intervention studies were excluded. RESULTS: Of 159 studies identified, 26 met inclusion criteria. Findings from neuroimaging studies may help explain the relationship between brain mechanisms and behavioral aspects of dietary choice and inform patient education in obesity prevention. Awareness of this evidence is applicable to nursing education efforts. This review contributes several recommendations that should be considered by nurses providing individualized weight-loss education. LINKING EVIDENCE TO ACTION: Nurses engaged in patient education for obesity prevention should consider personalized interventions that cultivate internal awareness for dietary adherence, self-care, exercise, hydration, and mood state; avoid using caloric deprivation approaches, such as skipping breakfast, for weight-loss interventions; and note the importance of individualized obesity prevention and weight-loss education.

Sex Differences in the Association Between Cyberbullying Victimization and Mental Health, Substance Use, and Suicidal Ideation in Adolescents.

OBJECTIVE: To examine sex differences in the association between cyberbullying victimization and mental health (psychological distress and delinquency), substance use-related outcomes (drug and tobacco use, binge drinking), and suicide ideation among adolescents. METHOD: Data were obtained from the Ontario Student Drug Use and Health Survey (OSDUHS; 2013, N=10,272, grade 7 to 12). The sample for analysis included 4,940 students with a mean age of 15.1 years (43.3% male). A series of multi-level, binary, logistic regression models were conducted separately for female and male adolescents to quantify the strength of associations between cyberbullying victimization and study outcomes, after accounting for traditional forms of bullying and demographic covariates. RESULTS: Female adolescents reported significantly higher prevalence of cyberbullying victimization (once, 9.4%; twice or more, 13.3%) as compared with male adolescents (once, 8.3%, twice or more, 7.8%). Exposure to cyberbullying victimization was associated with an increased odds for psychological distress, suicide ideation, and delinquency among both female and male adolescents (adjusted odds ratios ranged from 1.76 to 4.63); although, the effects were more pronounced in females. Among females, but not males, the odds of reporting psychological distress, suicide ideation, and delinquency increased (in a step-wise fashion) with more frequent exposure to cyberbullying victimization. Cyberbullying victimization was associated with an increased odds of adolescent substance use only among females. CONCLUSION: Adolescents exposed to cyberbullying victimization demonstrate an increased odds of poorer mental health, substance use outcomes, and suicide ideation. The current study reveals increased risk among female adolescents as compared with male adolescents. These findings lend support for the need to develop and evaluate targeted preventative interventions specifically tailored for female and male adolescents.

CFTR modulator theratyping: Current status, gaps and future directions.

BACKGROUND: New drugs that improve the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with discreet disease-causing variants have been successfully developed for cystic fibrosis (CF) patients. Preclinical model systems have played a critical role in this process, and have the potential to inform researchers and CF healthcare providers regarding the nature of defects in rare CFTR variants, and to potentially support use of modulator therapies in new populations. METHODS: The Cystic Fibrosis Foundation (CFF) assembled a workshop of international experts to discuss the use of preclinical model systems to examine the nature of CF-causing variants in CFTR and the role of in vitro CFTR modulator testing to inform in vivo modulator use. The theme of the workshop was centered on CFTR theratyping, a term that encompasses the use of CFTR modulators to define defects in CFTR in vitro, with application to both common and rare CFTR variants. RESULTS: Several preclinical model systems were identified in various stages of maturity, ranging from the expression of CFTR variant cDNA in stable cell lines to examination of cells derived from CF patients, including the gastrointestinal tract, the respiratory tree, and the blood. Common themes included the ongoing need for standardization, validation, and defining the predictive capacity of data derived from model systems to estimate clinical outcomes from modulator-treated CF patients. CONCLUSIONS: CFTR modulator theratyping is a novel and rapidly evolving field that has the potential to identify rare CFTR variants that are responsive to approved drugs or drugs in development.

Eradication of persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.

BACKGROUND: The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in individuals with cystic fibrosis (CF) has increased significantly. While studies demonstrate that persistent MRSA infection in CF is associated with poor clinical outcomes, there are no randomized controlled studies informing management. METHODS: The Persistent MRSA Eradication Protocol was a double-blind, randomized, placebo-controlled study investigating a comprehensive 28-day treatment regimen with or without inhaled vancomycin for eradication of MRSA. Eligible participants had CF and documented persistent MRSA infection. All participants received oral antibiotics, topical decontamination, and environmental cleaning and were randomized to receive inhaled vancomycin or inhaled placebo. The primary outcome was the difference in MRSA eradication rates one month after completion of the treatment protocol. RESULTS: 29 participants were randomized. Four subjects in the inhaled vancomycin group required withdrawal from the study for bronchospasm before outcome data were collected and were excluded from analysis. There was no difference in the primary outcome: 2/10 (20%) of subjects in the intervention group and 3/15 (20%) in the placebo group had a MRSA negative sputum culture one month after treatment. There were no statistically significant differences in the rates of MRSA eradication at the end of treatment or three months after treatment completion. CONCLUSIONS: This study suggests that persistent MRSA infection is difficult to eradicate, even with multimodal antibiotics. The use of a single course of inhaled vancomycin may not lead to higher rates of MRSA eradication in individuals with CF and may be associated with bronchospasm. FUND: This trial was financially supported by the Cystic Fibrosis Foundation.

Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV1.

BACKGROUND: Improved lung function and fewer pulmonary exacerbations (PEx) were observed with lumacaftor/ivacaftor (LUM/IVA) in patients with cystic fibrosis homozygous for F508del. It is unknown whether PEx reduction extends to patients without early lung function improvement. METHODS: Post hoc analyses of pooled phase 3 data (NCT01807923, NCT01807949) categorized LUM/IVA-treated patients by percent predicted forced expiratory volume in 1 s (ppFEV1) change from baseline to day 15 into threshold categories (absolute change ≤0 vs >0; relative change <5% vs ≥5%) and compared PEx rates vs placebo. RESULTS: LUM (400 mg q12h)/IVA (250 mg q12h)-treated patients (n = 369) experienced significantly fewer PEx vs placebo, regardless of threshold category. With LUM/IVA, PEx rate per patient per year was 0.60 for those with absolute change in ppFEV1 > 0 and 0.85 for those with absolute change ≤0 (respective rate ratios vs placebo [95% CI]: 0.53 [0.40-0.69; P < .0001], 0.74 [0.55-0.99; P = .04]). CONCLUSIONS: LUM/IVA significantly reduced PEx, even in patients without early lung function improvement.

Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR.

BACKGROUND: The ability to restore cystic fibrosis transmembrane regulator (CFTR) function with effective small molecule modulators in patients with cystic fibrosis provides an opportunity to study relationships between CFTR ion channel function, organ level physiology, and clinical outcomes. METHODS: We performed a multisite, prospective, observational study of ivacaftor, prescribed in patients with the G551D-CFTR mutation. Measurements of lung mucociliary clearance (MCC) were performed before and after treatment initiation (1 and 3 months), in parallel with clinical outcome measures. RESULTS: Marked acceleration in whole lung, central lung, and peripheral lung MCC was observed 1 month after beginning ivacaftor and was sustained at 3 months. Improvements in MCC correlated with improvements in forced expiratory volume in the first second (FEV1) but not sweat chloride or symptom scores. CONCLUSIONS: Restoration of CFTR activity with ivacaftor led to significant improvements in MCC. This physiologic assessment provides a means to characterize future CFTR modulator therapies and may help to predict improvements in lung function. TRIAL REGISTRATION: ClinicialTrials.gov, NCT01521338. FUNDING: CFF Therapeutics (GOAL11K1).

Risk factors for persistent Aspergillus respiratory isolation in cystic fibrosis.

BACKGROUND: Aspergillus species are increasingly detected in the respiratory tracts of individuals with cystic fibrosis (CF), and chronic Aspergillus fumigatus is associated with more frequent hospitalizations for pulmonary exacerbations. However, patient and clinical factors that may contribute to the acquisition of persistent Aspergillus infection have yet to be identified. The objective of this study was to identify risk factors for development of Aspergillus respiratory isolation in CF. METHODS: A retrospective cohort study of participants in the CF Foundation Patient Registry between 2006 and 2012 was conducted. Generalized estimating equation models were used to evaluate the association between the development of persistent Aspergillus respiratory isolation and individual level demographic and clinical characteristics. RESULTS: Among 16,095 individuals with CF followed from 2006 to 2012, 1541 (9.6%) subjects developed persistent Aspergillus isolation. White race (Odds Ratio [OR] 1.74, 95% confidence interval 1.23, 2.48, p<0.001) and pancreatic insufficiency (OR 1.50, 95% CI 1.09, 2.06, p<0.001) were found to be risk factors for persistent Aspergillus isolation. Chronic therapies, including inhaled antibiotics (OR 1.33; 95% CI 1.21, 1.46), macrolides (OR 1.23, 95% CI 1.14, 1.32, p<0.001), and inhaled corticosteroids (OR 1.13, 95% CI 1.04, 1.20, p<0.001) were also independently associated with an increased risk for persistent Aspergillus isolation. CONCLUSIONS: We identified macrolides and inhaled antibiotics, which individually have been shown to improve CF outcomes, and inhaled corticosteroids as risk factors for developing persistent Aspergillus isolation. Further work is needed to determine whether these associations are causal or due to confounding by other factors.

Frequency of small-colony variants and antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus in cystic fibrosis patients.

BACKGROUND: Small-colony variants (SCVs) are a distinct phenotype of Staphylococcus aureus, known for their role in chronic, difficult to treat infections, including cystic fibrosis (CF) lung disease. The goal of this study was to characterize SCV MRSA infection in an adult and pediatric CF population and to identify antibiotic susceptibility patterns unique to SCV MRSA. METHODS: We recovered methicillin-resistant S. aureus (MRSA) from respiratory culture samples from CF patients at the Johns Hopkins Hospital during a 6month study period. RESULTS: Of 1161 samples, 200 isolates (17%) were identified as MRSA, and 37 isolates from 28 patients were identified as SCV MRSA. A higher proportion of MRSA was found among SCV isolates (37/66, 56%) compared to normal colony variant (NCV) isolates (163/417, 39%), p=0.02. All SCV MRSA isolates from individual patients were susceptible to vancomycin and ceftaroline, but they demonstrated higher rates of antibiotic resistance to trimethoprim/sulfamethoxazole, moxifloxacin, and erythromycin, compared to NCV MRSA isolates. Additionally, individuals with SCV MRSA had lower lung function, higher rates of persistent MRSA infection, and higher rates of previous antibiotic use, compared to individuals with NCV MRSA. CONCLUSIONS: A significant proportion of MRSA isolates recovered from patients with CF have the SCV morphology. Compared to individuals with NCV MRSA, those with SCV MRSA have higher rates of persistent MRSA infection and lower lung function. SCV MRSA isolates were more resistant than NCV, but they are highly susceptible to vancomycin, linezolid and ceftaroline.

Airway Mucosal Host Defense Is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity.

RATIONALE: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that more than 50% of the variability reflects non-cystic fibrosis transmembrane conductance regulator (CFTR) genetic variation; however, the full extent of the pertinent genetic variation is not known. OBJECTIVES: We sought to identify novel CF disease-modifying mechanisms using an integrated approach based on analyzing "in vivo" CF airway epithelial gene expression complemented with genome-wide association study (GWAS) data. METHODS: Nasal mucosal RNA from 134 patients with CF was used for RNA sequencing. We tested for associations of transcriptomic (gene expression) data with a quantitative phenotype of CF lung disease severity. Pathway analysis of CF GWAS data (n = 5,659 patients) was performed to identify novel pathways and assess the concordance of genomic and transcriptomic data. Association of gene expression with previously identified CF GWAS risk alleles was also tested. MEASUREMENTS AND MAIN RESULTS: Significant evidence of heritable gene expression was identified. Gene expression pathways relevant to airway mucosal host defense were significantly associated with CF lung disease severity, including viral infection, inflammation/inflammatory signaling, lipid metabolism, apoptosis, ion transport, Phe508del CFTR processing, and innate immune responses, including HLA (human leukocyte antigen) genes. Ion transport and CFTR processing pathways, as well as HLA genes, were identified across differential gene expression and GWAS signals. CONCLUSIONS: Transcriptomic analyses of CF airway epithelia, coupled to genomic (GWAS) analyses, highlight the role of heritable host defense variation in determining the pathophysiology of CF lung disease. The identification of these pathways provides opportunities to pursue targeted interventions to improve CF lung health.

Home Monitoring of Patients with Cystic Fibrosis to Identify and Treat Acute Pulmonary Exacerbations. eICE Study Results.

RATIONALE: Individuals with cystic fibrosis (CF) experience frequent acute pulmonary exacerbations, which lead to decreased lung function and reduced quality of life. OBJECTIVES: The goal of this study was to determine if an intervention directed toward early detection of pulmonary exacerbations using home spirometry and symptom monitoring would result in slower decline in lung function than in control subjects. METHODS: We conducted a multicenter, randomized trial at 14 CF centers with subjects at least 14 years old. The early intervention arm subjects measured home spirometry and symptoms electronically twice per week. Sites were notified if a participant met criteria for an exacerbation and contacted participants to determine if treatment for acute exacerbation was required. Participants in the usual care arm were seen every 3 months and were asked to contact the site if they were concerned about worsening pulmonary symptoms. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the 52-week change in FEV1. Secondary outcomes included time to first exacerbation and subsequent exacerbation, quality of life, and change in weight. A total of 267 patients were randomized, and the study arms were well matched at baseline. There was no significant difference between study arms in 52-week mean change in FEV1 slope (mean slope difference, 0.00 L, 95% confidence interval, -0.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 95% confidence interval, 1.09 to 1.93; P = 0.01). Adverse events were not significantly different between treatment arms. CONCLUSIONS: An intervention of home monitoring among patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function. Clinical trial registered with www.clinicaltrials.gov (NCT01104402).

Risk factors for persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as an important pathogen in cystic fibrosis (CF). Over 25% of individuals in the United States with CF are found to have MRSA in respiratory culture specimens, and persistent MRSA infection has been associated with more rapid decline in lung function and increased mortality. The objective of this study was to investigate clinical and demographic characteristics that are associated with the development of persistent MRSA infection in a CF population. METHODS: This was a retrospective cohort study of individuals followed from 2002 to 2012 in the Cystic Fibrosis Foundation Patient Registry. A time-to-event analysis for the development of persistent MRSA infection was performed, and multivariable Cox proportional hazards models were constructed to identify risk factors for infection. RESULTS: The study cohort included 19,434 individuals, of which 5844 would develop persistent MRSA infection. In the adjusted model, pancreatic insufficiency (HR: 1.49; 95% CI: 1.29-1.72), CF related diabetes (HR: 1.13; 95% CI: 1.05-1.20), co-infection with P. aeruginosa (HR: 1.21; 95% CI: 1.13-1.28), and number of hospitalizations/year (HR: 1.09; 95% CI: 1.06-1.12) were all associated with increased risk, whereas higher socio-economic status (HR: 0.87; 95% CI: 0.82-0.93) was associated with a lower risk. Receiving care at a CF center with increased MRSA prevalence was associated with increased risk of MRSA infection: highest quartile (HR: 2.33; 95% CI: 2.13-2.56). CONCLUSIONS: No easily modifiable risk factors for persistent MRSA were identified in this study. However, several risk factors for patients at higher risk for persistent MRSA infection were identified, for example centers with a high baseline MRSA prevalence, and may be useful in designing center-specific MRSA infection prevention and control strategies and/or eradication protocols. Additional studies are needed in order to evaluate if attention to these risk factors can improve clinical outcomes.