Citations

Abstract Introduction Inhaled corticosteroid/fast-acting beta2-agonist combinations are recommended over albuterol-alone as rescue in asthma due to superior exacerbation reduction. In adults with asthma, BATURA and MANDALA demonstrated as-needed albuterol-budesonide 180/160 μg reduced the risk of severe exacerbation by 46% in mild and 28% in moderate-to-severe asthma for patients aged ≥18 years versus albuterol 180 μg. However, albuterol is the long-held rescue therapy standard for treatment of bronchoconstriction. In the ALbuterol-budesonide Treatment in Acute Airway Obstruction (ALTA) (NCT05555290) study, repetitive albuterol-budesonide 180/160 ug versus albuterol 180 ug treatment resulted in equally rapid improvement in lung function over 60 minutes and provided enhanced bronchodilation at 480 minutes post-mannitol challenge: least squares mean/LSM(standard error/SE) [95%CI] difference in ΔFEV1=91.2 (27.4) [36.7-145.7] mL. This post-hoc analysis of ALTA evaluated whether baseline lung function affects treatment response. Methods ALTA was a Phase 3b, multicenter, randomized, double-blind, 2-period, crossover study evaluating efficacy of repetitive albuterol-budesonide 180/160 μg vs albuterol 180 μg in adults with mild asthma experiencing ≥15% fall in FEV1 with cumulative mannitol exposure ≤635 mg. Inclusion criteria included use of short-acting beta2-agonist as the only pre-enrollment therapy for ≥4 weeks and pre-challenge FEV1 ≥1.500 L and 60%-<90% of predicted. Participants received albuterol-budesonide or albuterol at end-mannitol challenge (time 0) and 20, 40, and 60 minutes thereafter. FEV1 was assessed starting pre-mannitol challenge (-30 minutes) and over 480 minutes post-challenge. For participants with baseline FEV1 60%-<80% and 80%-<90% predicted, LSM(SE) [95%CI] difference between treatment arms in ΔFEV1 from time 0 min at 480 minutes was analyzed using a linear mixed effects model. Results 88 randomized participants receiving ≥1 dose of study drug were included: mean(SD) age=44.5(13.7) years; 56.8% female; mean(SD) FEV1=2.462(0.540) L (76.7[7.7]% predicted). 56 participants had baseline FEV1 ≥60%-<80% predicted; 32 had baseline FEV1 80%-<90% predicted. Percent fall in FEV1 post-challenge was similar between lung function subgroups. Improvement in FEV1 post-mannitol (time 0 min) at 480 min was greater with albuterol-budesonide vs albuterol treatment for both FEV1 subgroups: LSM(SE) [95%CI] difference 71.0(29.8) [11.0-131.0] mL, p = 0.021 in the lower and 114.0(55.1) [1.0-227.0] mL, p = 0.048 in the higher baseline FEV1 participants (Figure). There was no significant difference in the treatment by subgroup interaction, suggesting consistent treatment efficacy between subgroups. Conclusions Albuterol-budesonide relieves acute obstruction better than albuterol over time in mild asthma whether or not baseline lung function falls within a normal range. This abstract is funded by: AstraZeneca

Context.— The Goldman criteria are widely used to categorize diagnostic discrepancies in autopsy reports for hospital quality assurance. Despite their adoption, little is known about how consistently they are applied across institutions. Objective.— To evaluate the interrater reliability among academic pathologists applying the Goldman criteria to classify missed diagnoses in autopsy cases. Design.— Thirty autopsy cases from 2 academic hospitals were reviewed by 5 experienced autopsy pathologists. Each reviewer independently assigned Goldman classification scores (class I–IV) to missed diagnoses based on the original 1983 definitions. Consensus was defined as at least 60% agreement (≥3 of 5 raters). Fleiss κ and Gwet AC1 were calculated to assess interrater reliability. Results.— A total of 196 missed diagnoses were identified by at least 1 rater. Only 26% (51 of 196) achieved a consensus Goldman classification, and just 4% (8 of 196) had unanimous classification agreement. Most diagnoses (65%; 127 of 196) were not identified by at least 3 raters. Among consensus classification ratings, 49% (25 of 51) were class IV. Fleiss κ was 0.176 (slight agreement) while Gwet AC1 was 0.390 (fair agreement). Collapsing major (classes I–II) and minor (classes III–IV) categories modestly improved agreement. Conclusions.— Interrater agreement in applying the Goldman criteria is only fair to moderate, suggesting significant subjectivity in their application. As the criteria are used for institutional comparison and quality metrics, efforts to standardize definitions and provide reviewer training are warranted to improve reproducibility and utility.

Abstract Background: Classic metaphyseal lesions (CMLs) are considered specific for child abuse, but the reliability of radiologists in distinguishing CMLs from metaphyseal variations is unclear. Objective: To evaluate whether radiologists can differentiate between CMLs and metaphyseal variations in the knees. Materials and Methods: We performed a retrospective review of distal femur and proximal tibia radiographs in children under two years of age who underwent skeletal surveys for suspected child abuse. The CML group included children diagnosed with abuse and reported CMLs. The metaphyseal variation group included children not diagnosed with abuse, with reported metaphyseal variations and either no fractures or an isolated skull fracture. Radiographs were trimmed to exclude other injuries. Four pediatric and four general radiologists reviewed anonymized studies and categorized each case as CML, metaphyseal variation, normal, or indeterminate, with confidence levels (high, moderate, low). We analyzed diagnoses with moderate or high confidence. Interobserver agreement was assessed using kappa statistics. Results: There were 48 children with CMLs (40 initial, 38 follow-up) and 27 with metaphyseal variations (20 initial, 12 follow-up). Metaphyseal fragmentation was the most common variation, identified in 259 of 356 femurs (72.8%) and 69 of 83 tibias (83.1%). Fragmentations were most frequently located in the posterior or medial metaphysis, or both, in 257 of 259 femurs (99.2%) (257/259) and 68 of 69 tibias (98.6%). In the CML group, 34 of 115 initial CML diagnoses (29.4%) were read on follow-up as either metaphyseal variation (n=17) or normal (n=17). In contrast, in the metaphyseal variation group, only one follow-up case was diagnosed as a CML; the remainder were diagnosed as metaphyseal variation (n=22) or normal (n=2). Diagnostic performance for CML demonstrated high specificity (90.7%) and positive predictive value (94.9%), with moderate accuracy (76.1%), sensitivity (70.2%), and negative predictive value (55.2%). Interobserver agreement was substantial, with a mean kappa of 0.61. Conclusion: Radiologists demonstrated substantial agreement and high specificity in distinguishing CMLs from metaphyseal variations. Metaphyseal fragmentation was the most common variation and was uncommonly diagnosed as CML on follow-up.

ABSTRACTObjectivesTo achieve consensus among expert laser surgeons on standards for the prevention and management of adverse events from fully ablative laser resurfacing of the face.Materials and MethodsDelphi study with two rounds of ratings and revisions until consensus was achieved. The draft set of statements was developed by a steering committee based on expert clinical experience. This was followed by two rounds of rating and revisions completed by an expert panel, then a virtual consensus meeting. In both rounds, respondents rated the draft statements on a 9‐point Likert scale (1 = strongly disagree; 9 = strongly agree) and optionally provided comments. The consensus meeting was supplemented by the results of a systematic review of the literature (from 2000 to 2023).ResultsTwo rounds of Delphi survey were completed by 34 participants across four countries. Represented specialties were dermatology, facial plastic surgery, plastic surgery, and oculoplastic surgery. The initial 105 statements from round 1 expanded to 112 in round 2, with 96 statements achieving consensus. These included possible adverse events (11 statements); absolute and relative contraindications to treatment (5 statements); preoperative care and antimicrobial prophylaxis precautions (16 statements); intraoperative precautions (17 statements); postoperative care (21 statements); monitoring for and management of infection (16 statements); management of pigmentation changes (6 statements); and management of scarring and incipient scarring (4 statements).ConclusionAn international consensus statement was developed for the prevention and management of complications associated with fully ablative laser resurfacing of the face. While expert practices vary, key factors for optimizing outcomes include careful patient selection, counseling, and meticulous pre‐ and postoperative care. Further research will improve our understanding of this treatment technique.

Abstract RATIONALE: Albuterol-budesonide 180/160 µg is indicated in the US for as-needed treatment or prevention of bronchoconstriction and to reduce risk of exacerbations in patients ≥18 years old with asthma. The objective of the ALbuterol-budesonide Treatment in Acute airway obstruction (ALTA) study (NCT05555290) is to assess comparative efficacy, safety, and mechanisms of action of albuterol-budesonide 180/160 µg versus albuterol 180 µg in treating and preventing bronchoconstriction. This report describes the clinical profiles of patients meeting criteria for randomization into the trial. METHODS: ALTA is a phase 3b, multicenter, randomized, double-blind, 2-period, cross-over study evaluating the effects of repetitive dosing of albuterol-budesonide 180/160 µg versus albuterol 180 µg for treating adults treated as intermittent asthma and experiencing acute airway obstruction induced by repeated mannitol challenges. Inclusion criteria evaluated during screening include asthma diagnosis ≥6 months, prescribed and utilizing albuterol as the only asthma treatment for ≥4 weeks, pre-bronchodilator FEV1 ≥1.50 L and FEV1 ≥60% to <90% predicted, and positive response to a mannitol challenge (decrease in FEV1≥15% at ≤635 mg cumulative mannitol dose). Exclusion criteria include clinically significant lung disease other than asthma; any smoking in the prior 6 months or ≥10 pack-year smoking history; or a clinical encounter for asthma worsening within the past 4 weeks. RESULTS: Thus far, 84 patients have met the criteria for randomization into ALTA. Mean(SD) age=44.9(13.7) years, 56.0% female, 40.5% African American, 9.5% Hispanic/Latino. Clinical characteristics include 10.7% with 1 prior-year severe exacerbation; mean(SD) fractional exhaled nitric oxide=37.0(37.4) ppb; mean(SD) baseline pre-bronchodilator FEV1=2.464(0.538) L; mean(SD) baseline percent predicted FEV1=76.7(7.9)%; mean(SD) % fall in FEV1 with mannitol challenge=22.1(7.3)% at a mean(SD) cumulative mannitol dose of 146.4(176.3) mg. Despite being treated for intermittent asthma, based upon symptoms, lung function, and exacerbation history, no patients met NAEPP 2007 criteria for intermittent disease, and 13.1% fell into the mild, 78.6% moderate, and 8.3% severe persistent asthma categories (Figure). With respect to asthma control, as measured by Asthma Impairment and Risk Questionnaire scores, 60.7% had well-controlled, 20.2% not well-controlled, and 19.1% very poorly controlled disease. CONCLUSION: The baseline characteristics of patients in the ALTA study reveal that patients treated as intermittent asthma exhibit heterogeneity in clinical characteristics, airway hyper-reactivity, T2 inflammation, and disease severity and control. Additional genomic and biomarker data are forthcoming and altogether will provide an opportunity to address the mechanism of albuterol and budesonide interactions in a broad spectrum of asthma phenotypes.

Aims: Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status. Mitochondrial transmembrane potential, superoxide production, and mass were measured by flow cytometry in fresh platelets. Metabolomics analysis was performed on plasma samples. Global arginine bioavailability was calculated as the ratio of arginine/(ornithine+citrulline). Results: Global arginine bioavailability is consistently lower than controls in all PH groups. Although the mitochondrial mass is similar across all PH groups and controls, superoxide production and transmembrane potential vary across groups. Mitochondrial superoxide is higher in group 1 PAH and lowest in group 3 compared with other groups, while transmembrane potential is lower in group 1 PAH than controls or group 3. The alterations in mitochondrial functions of group 1 PAH are associated with changes in fatty acid metabolism. Mitochondrial transmembrane potential in group 1 PAH is associated with transplant-free survival. Conclusion: While alterations in mitochondrial function are found in all PH groups, group 1 PAH has a unique mitochondrial phenotype with greater superoxide and lower transmembrane potential linked to fatty acid metabolism, and clinically to survival. Antioxid. Redox Signal. 42, 361–377.

Significance Statement Changes in albuminuria and GFR slope are individually used as surrogate end points in clinical trials of CKD progression, and studies have demonstrated that each is associated with treatment effects on clinical end points. In this study, the authors sought to develop a conceptual framework that combines both surrogate end points to better predict treatment effects on clinical end points in Phase 2 trials. The results demonstrate that information from the combined treatment effects on albuminuria and GFR slope improves the prediction of treatment effects on the clinical end point for Phase 2 trials with sample sizes between 100 and 200 patients and duration of follow-up ranging from 1 to 2 years. These findings may help inform design of clinical trials for interventions aimed at slowing CKD progression. Background Changes in log urinary albumin-to-creatinine ratio (UACR) and GFR slope are individually used as surrogate end points in clinical trials of CKD progression. Whether combining these surrogate end points might strengthen inferences about clinical benefit is unknown. Methods Using Bayesian meta-regressions across 41 randomized trials of CKD progression, we characterized the combined relationship between the treatment effects on the clinical end point (sustained doubling of serum creatinine, GFR <15 ml/min per 1.73 m 2 , or kidney failure) and treatment effects on UACR change and chronic GFR slope after 3 months. We applied the results to the design of Phase 2 trials on the basis of UACR change and chronic GFR slope in combination. Results Treatment effects on the clinical end point were strongly associated with the combination of treatment effects on UACR change and chronic slope. The posterior median meta-regression coefficients for treatment effects were −0.41 (95% Bayesian Credible Interval, −0.64 to −0.17) per 1 ml/min per 1.73 m 2 per year for the treatment effect on GFR slope and −0.06 (95% Bayesian Credible Interval, −0.90 to 0.77) for the treatment effect on UACR change. The predicted probability of clinical benefit when considering both surrogates was determined primarily by estimated treatment effects on UACR when sample size was small (approximately 60 patients per treatment arm) and follow-up brief (approximately 1 year), with the importance of GFR slope increasing for larger sample sizes and longer follow-up. Conclusions In Phase 2 trials of CKD with sample sizes of 100–200 patients per arm and follow-up between 1 and 2 years, combining information from treatment effects on UACR change and GFR slope improved the prediction of treatment effects on clinical end points.

Importance Laser-assisted drug delivery (LADD) is used for various medical and cosmetic applications. However, there is insufficient evidence-based guidance to assist clinicians performing LADD. Objective To develop recommendations for the safe and effective use of LADD. Evidence Review A systematic literature review of Cochrane Central Register of Controlled Trials, Embase, and MEDLINE was conducted in December 2019 to identify publications reporting research on LADD. A multidisciplinary panel was convened to draft recommendations informed by the systematic review; they were refined through 2 rounds of Delphi survey, 2 consensus meetings, and iterative review by all panelists until unanimous consensus was achieved. Findings Of the 48 published studies of ablative fractional LADD that met inclusion criteria, 4 were cosmetic studies; 21, oncologic; and 23, medical (not cosmetic/oncologic), and 6 publications of nonablative fractional LADD were included at the request of the expert panel, producing a total of 54 studies. Thirty-four studies (63.0%) were deemed to have low risk of bias, 17 studies (31.5%) had moderate risk, and 3 (5.5%) had serious risk. The key findings that informed the guidelines developed by the expert panel were as follows: LADD is safe in adults and adolescents (≥12 years) with all Fitzpatrick skin types and in patients with immunosuppression; it is an effective treatment for actinic keratosis, cutaneous squamous cell carcinoma in situ, actinic cheilitis, hypertrophic scars, and keloids; it is useful for epidermal and dermal analgesia; drug delivery may be increased through the application of heat, pressure, or occlusion, or by using an aqueous drug solution; laser settings should be selected to ensure that channel diameter is greater than the delivered molecule; antibiotic prophylaxis is not recommended, except with impaired wound healing; antiviral prophylaxis is recommended when treating the face and genitalia; and antifungal prophylaxis is not recommended. The guideline’s 15 recommendations address 5 areas of LADD use: (I) indications and contraindications; (II) parameters to report; (III) optimization of drug delivery; (IV) safety considerations; and (V) prophylaxis for bacterial, viral, and fungal infections. Conclusions and Relevance This systematic review and Delphi consensus approach culminated in an evidence-based clinical practice guideline for safe and effective use of LADD in a variety of applications. Future research will further improve our understanding of this novel treatment technique.

Study Design: This was an observational study. Objectives: This study aims to determine the correlation between patient-reported outcomes (PROs) pulled from a national spine registry and physician ratings from physician review websites (PRWs). Summary of Background Data: PRWs are frequently utilized by patients to make health care decisions; however, many PRWs appear to incorporate subjective experiences unrelated to a surgeon’s clinical performance into ratings. As such, their utility as a health care decision-making tool remains unclear. Materials and Methods: This study evaluated 8834 patients from the Quality Outcomes Database (QOD) who underwent 1-level elective lumbar spine surgery. The lumbar module of QOD was queried to rank 124 surgeons using PROs (Oswestry Disability Index, EuroQOL, Numerical Rating Scale—back/leg pain, and patient satisfaction). The QOD PRO-ranking system was compared against PRWs including Healthgrades, Vitals, WebMD, and Google. The Spearman correlation coefficients, Kruskal-Wallis tests, and multiple linear regression models were used for statistical comparison. The primary outcome was the correlation between PRW scores and PROs. Results: Surgeon PRO-derived ranking showed high intercorrelational congruence with coefficients between the 3 PROs (Oswestry Disability Index, EuroQOL, Numerical Rating Scale back/leg) ranging between 0.70 and 0.88. Low correlations were observed between PRO-derived rankings and PRWs, ranging from 0.23 to 0.37. Healthgrades performed most similarly to PRO-derived rankings, correlating best with patient satisfaction, though the correlation was low (ρ=0.37). Conclusions: While PRWs are often used to evaluate surgeon competency, these results demonstrate they poorly correlate with a surgeon’s clinical ability measured by PROs. PRWs should be used with caution when making health care decisions by patients, payers, and administrators. Level of Evidence: Level III.