A randomised trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 s (FEV1) % pred in CF pulmonary exacerbations not responding to antibiotic therapy. METHODS: This was a randomised, double-blind, placebo-controlled trial in pwCF treated with intravenous antibiotics for a pulmonary exacerbation. At day 7, those who had not returned to >90% baseline FEV1 % pred were randomised to adjuvant prednisone 1 mg·kg-1 twice daily (maximum 60 mg·day-1) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline FEV1 % pred at day 14 of i.v. antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomised. 50% of subjects in the prednisone group recovered baseline FEV1 on day 14 compared with 39% of subjects in the placebo group (difference of 11%, 95% CI -11-34%; p=0.34). The mean±sd change in FEV1 % pred from day 7 to day 14 was 6.8±8.8% predicted in the prednisone group and 4.6±6.9% predicted in the placebo group (mean difference 2.2% predicted, 95% CI -1.5-5.9%; p=0.24). Time to subsequent exacerbation was not prolonged in prednisone-treated subjects (hazard ratio 0.83, 95% CI 0.45-1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in FEV1 % pred recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of i.v. antibiotic therapy for pulmonary exacerbations.

Carbon Footprint Reduction Associated With Multidisciplinary Pediatric Airway Clinics: A Program Evaluation Study.

Objective: Health care is a significant contributor to the climate crisis. Multidisciplinary clinics (MDC) may reduce carbon emissions by combining multiple appointments into one. This is the first program evaluation study to quantify the carbon footprint associated with multidisciplinary pediatric airway clinics. Study Design: Retrospective. Setting: Children's Hospital at London Health Sciences Center, London, Canada. Methods: Pediatric airway MDC allows patients to see otolaryngology and respirology in one appointment. The carbon and financial savings (Canadian Dollars) of all patients attending the MDC from January 1, 2018 to December 31, 2022 were calculated. Patient postal codes and institutional parking rates were inputted into the CASCADES carbon accounting tool. Total distance was divided into unsustainable (vehicles) and sustainable (transit, walking, cycling) transportation to calculate carbon emissions. Travel costs included cost/kilometer for vehicles (maintenance, license/registration, insurance, fuel) and costs/ride for transit. Results: A total of 560 MDC appointments for 300 patients saved 77,785 km. Total carbon emissions saved from travel averted was 16.21 tonnes. The total carbon emissions saved, minus public transit, was 15.60 tonnes. Using the Natural Resources Canada Greenhouse Gas Equivalencies Calculator, 16.21 tonnes are approximately equivalent to 5 passenger vehicles, 6906 L of gasoline, 3.8 homes' energy, and 10.8 homes' electricity use for one year, 36.6 barrels of oil consumed, and 675 propane cylinders. Travel costs of $28,891.83 (no parking), $30,519.40 ($4 minimum parking fee), or $33,774.55 ($12 maximum parking fee) were saved. Conclusion: MDC effectively reduced carbon emissions and offered patients financial savings. Similar models can be adapted across institutions to help mitigate climate change.

Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing.

Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.