Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study.

BACKGROUND: MRT5005, a codon-optimized CFTR mRNA, delivered by aerosol in lipid nanoparticles, was designed as a genotype-agnostic treatment for CF lung disease. METHODS: This was a randomized, double-blind, placebo-controlled Phase 1/2 study performed in the US. Adults with 2 severe class I and/or II CFTR mutations and baseline ppFEV1 values between 50 and 90% were randomized 3:1 (MRT5005: placebo). Six dose levels of MRT5005 (4, 8, 12, 16, 20, and 24 mg) or placebo (0.9% Sodium Chloride) were administered by nebulization. The single ascending dose cohort was treated over a range from 8 to 24 mg; the multiple ascending dose cohort received five weekly doses (range 8-20 mg); and the daily dosing cohort received five daily doses (4 mg). RESULTS: A total of 42 subjects were assigned to MRT5005 [31] or placebo [11]. A total of 14 febrile reactions were observed in 10 MRT5005-treated participants, which were mild [3] or moderate [11] in severity; two subjects discontinued related to these events. Additionally, two MRT5005-treated patients experienced hypersensitivity reactions, which were managed conservatively. The most common treatment emergent adverse events were cough and headache. No consistent effects on FEV1 were noted. CONCLUSIONS: MRT5005 was generally safe and well tolerated through 28 days of follow-up after the last dose, though febrile and hypersensitivity reactions were noted. The majority of these reactions resolved within 1-2 days with supportive care allowing continued treatment with MRT5005 and careful monitoring. In this small first-in-human study, FEV1 remained stable after treatment, but no beneficial effects on FEV1 were observed.

Factors associated with receiving CF care and use of telehealth in 2020 among persons with Cystic Fibrosis in the United States.

BACKGROUND: The COVID-19 pandemic resulted in the use of telehealth to deliver the cystic fibrosis (CF) care model, which recommends routine follow-up for monitoring of nutritional status, bacterial culture surveillance, pulmonary function testing, and screening for CF-related complications such as diabetes or osteoporosis. METHODS: The objective of this study was to use Cystic Fibrosis Foundation Patient Registry (CFFPR) data to quantify the extent to which persons with CF received the recommended components of the care model in 2019 versus 2020. A risk factor analysis was implemented to identify patient characteristics associated with attaining the recommended CF care and use of any telehealth using multivariable logistic regression. RESULTS: A total of 28,132 CFFPR participants were included in the study. The proportion of individuals meeting the recommendations for CF care was lower in 2020 for every indicator, and lower in adults compared to children. In adults, demographic, socioeconomic and CF-related disease covariates were significantly associated with both achieving an aggregate level of care and use of telehealth. In the pediatric population, minority race/ethnicity and markers of lower socioeconomic status were associated with a lower odds of telehealth use. In all analyses, having received the recommended level of care in 2019 was associated with a higher odds of both reported telehealth use and achieving the recommended elements of the CF care model in 2020. CONCLUSION: Fewer participants met recommendations for care in 2020 despite widespread use of telehealth, and use of telehealth did not equate to adherence to all aspects of CF care.

ASXL1 and DNMT3A mutation in a cytogenetically normal B3 thymoma.

The molecular drivers of thymoma are poorly understood. Outside of the identification of rarely occurring epidermal growth factor receptor and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog mutations via candidate gene sequencing, mutations in common cancer genes have yet to be observed. Only a single thymoma genome sequence has been previously reported, with no mutations in known cancer genes identified. Thus, we attempted to identify somatic driver mutations in a cytogenetically normal thymoma. A stage IVB type B3 thymoma from a 47-year-old male of Asian descent with no history of myasthenia gravis or other autoimmune condition was genomically evaluated. Exome sequencing and low-pass whole-genome sequencing was performed to identify somatic point mutations, copy number changes and structural variants. Mutations in known tumor suppressors DNMT3A (p.G728D) and ASXL1 (p.E657fs), consistent with mutations of known consequence in acute myeloid leukemia, were identified. Contrary to a previous report, this finding suggests the genetic etiology of thymomas may not be fundamentally distinct from other tumor types. Rather, these findings suggest that further sequencing of cytogenetically normal thymoma samples should reveal the specific molecular drivers of thymoma.

The association of socioeconomic status with outcomes in cystic fibrosis patients in the United States.

There is considerable variability in the clinical course of disease in cystic fibrosis (CF). Although currently unidentified modifier genes might explain some of this heterogeneity, other factors are probably contributory. Socioeconomic status (SES) is an important predictor of health status in many chronic polygenic diseases, but its role in CF has not been systematically evaluated. We performed a historical cohort analysis of pediatric CF patients in the United States using National Cystic Fibrosis Foundation Patient Registry (NCFPR) data for 1986 to 1994, and used Medicaid status as a proxy for low SES. The adjusted risk of death was 3.65 times higher (95% confidence interval [CI]: 3.03 to 4.40) for Medicaid patients than for those not receiving Medicaid. The percent predicted FEV(1) of surviving Medicaid patients was less by 9.1% (95% CI: 6.9 to 11.2). Medicaid patients were 2.19 times more likely to be below the 5th percentile for weight (95% CI: 1.91 to 2.51) and 2.22 times more likely to be below the 5th percentile for height (95% CI: 1.95 to 2.52) than were non-Medicaid patients. Medicaid patients were 1.60 times more likely to require treatment for a pulmonary exacerbation (95% CI: 1.29 to 1.98). There was no difference in the number of outpatient clinic visits for Medicaid and non-Medicaid patients. We conclude that low SES is associated with significantly poorer outcomes in children with CF. Barriers in access to specialty health care do not seem to explain this difference. Further study is indicated to determine what adverse environmental factors might cluster in CF patients of low SES to cause worse outcomes.

High-resolution inspiratory and expiratory CT in older children and adults with bronchopulmonary dysplasia.

OBJECTIVE: The objective of this study is to correlate high-resolution inspiratory and expiratory CT findings with pulmonary function results in older children and adults who have bronchopulmonary dysplasia. SUBJECTS AND METHODS: High-resolution inspiratory and expiratory CT of the thorax was performed prospectively on 26 patients (16 male, 10 female) with a clinical history of bronchopulmonary dysplasia. The median age was 10 years old (range, 5-18 years). High-resolution CT during inspiration was scored for areas of decreased density and evidence of interstitial lung disease; expiratory CT was scored for air trapping. Findings were correlated with pulmonary function measurements and clinical history. RESULTS: Twenty-four (92%) of the 26 patients had abnormal CT findings. Of these 24, 22 had reticular opacities and 18 had areas of architectural distortion. Twenty patients had areas of relatively decreased density. In 24 patients, air trapping was seen on expiratory CT. Abnormal pulmonary function correlated significantly (p < .05) with abnormal decreases in density, air trapping on expiratory CT, and architectural distortion. CONCLUSION: Abnormal findings on inspiratory and expiratory high-resolution CT of older children with bronchopulmonary dysplasia include scarring and air trapping with architectural distortion. The correlation between these findings and physiologic evidence of air trapping and obstructive lung disease was statistically significant.

Relationship between socioeconomic status and disease severity in cystic fibrosis.

OBJECTIVE: This study was carried out to evaluate whether patients with cystic fibrosis (CF) who are socioeconomically disadvantaged, have a different outcome than higher-income patients. Medicaid insurance coverage was used as a proxy of low family income. STUDY DESIGN: A cross-sectional analysis was performed on a group of patients younger than 21 years of age seen at the University of North Carolina CF Center in 1994. RESULTS: The difference in median age at diagnosis for Medicaid (132 days) and non-Medicaid (177 days) patients was not statistically significant (p = 0.17). Medicaid patients' mean maximum percent predicted forced expiratory volume in 1 second for the year was 11.6% less than that of the non-Medicaid group (p = 0.01); this difference was constant across age. Medicaid patients averaged 0.8 more admissions for the year (p < 0.01) and 8.8 more days (p < 0.01) in the hospital but received the same amount of outpatient intravenous therapy. They also had 1.20 more outpatient visits to the center during the year (p = 0.02). CONCLUSIONS: Medicaid patients with CF have worse lung function and require more treatment for pulmonary exacerbations than their more advantaged counter-parts. This difference appears to begin early in life, does not increase with age, and is not explained by inadequate access to outpatient specialty care or delayed diagnosis. Other explanations such as inadequate access to primary care, poor adherence to prescribed regimens, or greater exposure to pollutants (e.g., environmental tobacco smoke) are speculative.

Biliary ductal shave biopsy with use of the Simpson atherectomy catheter.

PURPOSE: The authors performed percutaneous biliary ductal shave biopsy through an existing transhepatic biliary drainage tract with use of the Simpson atherectomy catheter. The technical feasibility, sensitivity, and complications of this endoluminal biopsy method were studied when used for diagnosis of biliary ductal and pancreatic neoplasm. PATIENTS AND METHODS: Nineteen bile duct shave biopsies were performed in 18 patients with symptomatic biliary obstruction by using a 9-F Simpson directional atherectomy catheter. Seven of the 18 patients underwent nine negative percutaneous needle biopsies prior to undergoing percutaneous biliary drainage. Results of previous transcatheter brush biopsies performed through the transhepatic tract were negative in all patients. RESULTS: A histologic diagnosis was obtained in 15 of the 19 procedures (sensitivity, 0.79) and included cholangiocarcinoma (n = 7), pancreatic carcinoma (n = 5), metastatic carcinoma (n = 2), and primary sclerosing cholangitis (n = 1). Two complications occurred in the 19 procedures (10.5%), both transient but significant hemorrhage, one of which necessitated transfusion. CONCLUSIONS: Percutaneous biliary ductal shave biopsy with the Simpson atherectomy catheter can be performed successfully through the transhepatic approach and is a sensitive endoluminal biopsy technique, particularly in patients with tumors of the biliary tree that are not diagnosed by means of percutaneous needle biopsy or endoscopic methods. Disadvantages of this method include the high cost of the device and risk of hemorrhage. Atherectomy shave biopsy should be used cautiously and only after more conventional biopsy methods have been employed.

Aircraft disinsecting: the effectiveness of Freon-based and water-based phenothrin and permethrin aerosols.

In Miami, Florida, USA, passenger compartments of jet aircraft were disinsected at "blocks away". An application of a 20 g/litre Freon-based or water-based permethrin formulation at 35 mg of aerosol per 100 m(3) was 100% effective against caged mosquitos and flies. The flammability hazard of the sprays from water-based hydrocarbon aerosols was evaluated.

A comparison of Freon- and water-based insecticidal aerosols for aircraft disinsection.

In Miami, USA, passenger compartments of wide-bodied jet aircraft were disinsected at "blocks away" or while parked. The application of 2% Freon- and water-based formulations of (+)-phenothrin at about 35 g/100 m(3) was highly effective against mosquitos and flies in all instances. More basic research is needed on water-based aerosols.

Ammonium sulfate activation of phosphodiesterase in homogenates of larvae of the european corn borer.

European corn borer phosphodiesterase is highly activated by (NH4)2SO4 and moderately activated by NH4C1 (pH 7.6, 33 degrees). Vertebrate and crayfish diesterases, on the other hand, are inhibited by (NH4)2SO4. It is likely that (NH4)2SO4 causes some configurational change in the European corn borer phosphodiesterase molecule which results in the exposure of more active sites and hence greater enzyme activity. In in vitro tests caffeine (0.008 M) and theophylline (0.008 M) inhibit phosphodiesterase more effectively in European corn borer larvae than in crayfish, ovine, bovine, or rat tissue.

Aircraft disinfection: the physical and insecticidal characteristics of (+)-phenothrin applied by aerosol at "blocks away".

A 2% formulation of (+)-phenothrin dispensed from 340-g or break-off tip aerosol cans was highly effective against mosquitos in aircraft disinsection trials. Two minutes after application at "blocks away", the mass median diameter of the dispersed drops was 5.1-6.2 mum. The concentration of the insecticide in the cabin fell to 10% of the original concentration after 9.2 min. No odour or irritation was caused by the use of this insecticide.