BACKGROUND:Reproducible quantification of pulmonary edema on chest radiographs is challenging for bedside clinicians. The Radiographic Assessment of Lung Edema (RALE) score offers a structured, semi-quantitative approach with prognostic implications in acute respiratory failure (ARF), yet its clinical use is limited by the absence of standardized training. OBJECTIVE:To determine whether a standardized RALE training program, combined with expert feedback, improves inter-rater reliability across clinician experience levels. METHODS:We analyzed 4487 chest radiographs from 864 critically ill patients with ARF enrolled in a prospective registry. Sixteen physicians (1 expert and 15 reviewers-including 5 interns, 4 residents, 3 fellows, and 3 attendings) completed a 3-phase RALE training program: (i) independent review of instructional materials, (ii) a live virtual session led by the expert, and (iii) iterative practice with expert feedback on discrepant scores. All scoring was performed using the Pulmo-Annotator platform. We assessed inter-rater reliability using intraclass correlation coefficients (ICC), Bland-Altman analysis, and Deming regression, while stratifying performance by experience level and self-reported confidence. RESULTS:Inter-rater reliability improved following the training program, with ICC increasing from 0.89 (95% CI: 0.85-0.92) to 0.93 (95% CI: 0.90-0.95) after expert feedback. Fellows demonstrated the largest gain of ICC from 0.89 to 0.97, while interns and attendings maintained high reliability. Post-feedback analyses indicated reduced systematic bias. Residents exhibited the greatest variability and revised fewer scores post-feedback, despite equivalent exposure to feedback. Score distributions also varied by self-reported confidence, with greater variability among less experienced reviewers. CONCLUSION:Following a structured training program, radiographic edema scoring using the RALE framework demonstrated excellent inter-rater reliability, which further improved with targeted expert feedback. This structured training program, which incorporated standardized instructional materials and iterative feedback, demonstrated that RALE scoring is teachable across different levels of clinical experience and can be integrated into educational curricula to enhance consistency in chest radiograph interpretation. These findings provide a foundation for future work exploring the role of RALE training in broader research and clinical applications.
Abstract Background Both intrinsic and extrinsic determinants of red blood cell (RBC) physiology, including HbF and HbS concentration, cellular hydration, whole blood viscosity, hematocrit, nitric oxide bioavailability, and cellular adhesion molecules, contribute to sickle cell disease (SCD), vaso-occlusive events (VOEs), and chronic hemolytic anemia that can drive progressive end-organ injury. There remains an unmet need for novel therapies to prevent pain and other morbidities in SCD. Emerging preclinical and clinical evidence shows that decreasing iron availability through iron restriction can reduce intracellular HbS concentration (ie, mean corpuscular hemoglobin concentration [MCHC]) and, thereby liimiting HbS polymerization and RBC sickling. Thus, iron restriction may be a safe and effective strategy to reduce hemolytic and vaso-occlusive complications and their downstream sequelae in people with SCD. DISC-3405 is an investigational, novel, humanized IgG1 monoclonal antibody (mAb) that targets transmembrane serine protease 6 (TMPRSS6, also known as matriptase 2) to stimulate endogenous production of hepcidin, a peptide hormone secreted by hepatocytes and the key regulator of iron homeostasis. In a mouse model of SCD, treatment with r4K12B (a mouse analog of DISC-3405) resulted in iron-restricted erythropoiesis and a significant decrease in hemolysis markers (Giannini, 2024). In a randomized, placebo-controlled Phase 1 study in healthy volunteers (DISC-3405-101), DISC-3405 administered subcutaneously at doses between 37.5 to 300 mg was well-tolerated, significantly increased hepcidin production with corresponding reductions in serum iron levels, and reduced MCHC (Liu, 2025; Liu, 2024). DISC-3405 is anticipated to increase hepcidin levels, restrict iron, reduce MCHC, and potentially lower intracellular HbS concentration, thereby reducing HbS polymerization and sickling and potentially leading to reduced clinical sequelae in SCD. Methods This is a Phase 1b, open-label, multicenter, within-participant dose-escalation study enrolling up to 24 patients with SCD in the US to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and therapeutic effect of DISC-3405 (Figure 1). After a screening period of 42 days, eligible participants will be treated and followed for 20 weeks and given up to 3 dose levels (75 mg, 150 mg, 300 mg) administered every 4 to 8 weeks. After 20 weeks, participants can continue in an optional 12-week maintenance period where additional safety and efficacy measurements will continue to be assessed. The primary endpoint of the study is to determine the safety and tolerability profile of DISC-3405. The secondary endpoints include changes in markers of hemolysis and PK. Exploratory endpoints include patient-reported outcome measures, changes and incidence of clinical measures of SCD (e.g., VOEs, transfusions, hospitalizations), changes in markers of iron homeostasis, and measures of RBC deformability and whole blood viscosity. A safety review committee will aid in the monitoring of emerging data during the study to ensure ongoing safety of study participants. Eligible participants include adults aged 18 years or older with HbSS or HbSC and normal alpha globin gene screen, hemoglobin levels ≥7 g/dL (the first 2 participants must have hemoglobin ≥9 g/dL), reticulocyte counts >1.5 x upper limit of normal, transferrin saturation 15% or higher, and ferritin between 50 to 1000 ng/mL. Participants should have evidence of SCD-related complications, including 1 to 10 vaso-occlusive pain episodes in the past 12 months or other end-organ damage. Participants taking hydroxyurea, L-glutamine, or crizanlizumab will be eligible provided they have been on a stable dose for at least 2 months prior to screening. Key exclusion criteria include the need for chronic transfusion therapy, hospitalization within 14 days of screening, hepatic dysfunction, and estimated glomerular filtration rate of < 60 mL/min/1.73 m2. Results This study is in progress. Enrollment has initiated. Eleven sites in the US are planned to open for enrollment. Conclusions DISC-3405 is an investigational, novel mAb that stimulates endogenous production of hepcidin and leads to iron restriction, which may benefit individuals living with SCD. Additional details regarding the DISC-3405-102 study can be found at https://clinicaltrials.gov/study/NCT07187973.
Abstract Rationale The ATS’s recommendation for race-neutral spirometry flagged disability as a research priority. There is no prior published data from real-world disabled patients. The Promises to Address Comprehensive Toxics (PACT) Act recognizes sarcoidosis in Veterans as a presumptively service-connected disability. This offers an avenue to explore the impact of race-neutral interpretation on the adjudication of disability payments. Methods We conducted a population-based retrospective study using Veterans Health Administration (VHA) records. Study inclusion required Veterans to be enrolled in the VHA, have available spirometry data, and to have received care for diagnosis of sarcoidosis through the VHA or Medicare between 2002 and 2022. Age, sex, height, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio were extracted from spirometry nearest their time of diagnosis. We recorded whether every included participant had a current disability status connected to their sarcoidosis. We calculated each participant’s percent predicted values for FEV1 and FVC using both GLI-2012 and GLI-Global, then compared each approach’s resultant disability rating. We calculated VHA disability ratings using the chronic bronchitis option for pulmonary sarcoidosis as specified in the Code of Federal Regulations Title 38 Chapter 1 Part 4. Assuming a Veteran alone with no dependents, we extracted the monthly compensation from the 2025 current Veterans disability compensation rates table. We compared each participant’s disability ratings and payments under the two interpretative reference equations. Results Among a cohort of 26,708 with sarcoidosis, 3,551 participants met our study’s inclusion criteria. They were predominantly male (87%), with 51% falling in the age range of 51-70 years old. Most identified as either Black (48.5%) or White (46.5%). Their mean FEV1 was 2.69L ±0.82L. The mean FVC was 3.61L±0.97L. 14.5% had a VA disability status currently connected to their sarcoidosis diagnosis. Overall, the use of GLI-Global increased the proportion and severity of veterans eligible for disability status relative to the use of GLI-2012. This effect was most marked among Black veterans. While this did not affect payments for 78.2% of Black Veterans, 15% would see higher monthly payments under GLI-Global’s race-neutral interpretation (Figure 1). Consequently, the proportion of Black Veterans not qualifying for payments would almost halve, while the most severely affected 0.75% participants would see payments increased by over $400 monthly. Conclusions Despite the PACT Act, earned disability from sarcoidosis is severely underutilized among Veterans. Adoption of a race-neutral interpretation could significantly enhance prospective payments overall. This abstract is funded by: Nina Ireland Program for Lung Health
