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Abstract Rationale : Interprofessional providers (IPPs), such as nurses, pharmacists, and respiratory therapists, teaching physician trainees (“interprofessional teaching” [IPT]), may improve teamwork and quality of care in the intensive care unit (ICU). However, the role that IPPs play in physician trainee education in the ICU and their attitudes about IPT have not been well described. In this study, we explored the impact of IPPs on education for Pulmonary and Critical Care fellows and their perceptions regarding IPPs as teachers for medical trainees. Methods: Fellows from eight large academic medical centers with pulmonary and critical care fellowship programs located in the Northeast, Mid-Atlantic, Midwest and West Coast were invited to participate. Eligible participants included Internal Medicine-trained Pulmonary and Critical Care or Critical Care Medicine fellows in the first, second, or third year of fellowship training. All focus groups were led by a single study team member who facilitated sessions in-person at four sites and virtually at four sites. Focus group transcripts were analyzed using a framework approach, and inter-rater reliability testing was performed prior to coding each manuscript in full (Cohen's kappa = 0.77). Results: Focus groups were held at eight sites between March and July 2023. A total of 50 fellows participated, including 13 first year, 21 second year, and 12 third year fellows, all of whom had completed at least 8 weeks of medical ICU rotations during fellowship. Several themes emerged. Fellows identified the relevance of IPP teaching content, fellow bandwidth to learn from IPPs, and the perceived benefit of relationship building with IPPs as factors that made them ideal learners for IPT among medical trainees. Fellows described distinct teaching content from each IPP group, with nurses revealing the “hidden curriculum,” pharmacists providing specific concrete learning points and incorporating primary literature, and respiratory therapists teaching at the bedside. Identified barriers to IPT included fellows’ competing roles as both teacher and learner in limited time, IPPs having difficulty identifying learner needs at varying levels, and fellows’ uncertainty about whether IPPs view themselves as educators. Conclusions: Fellows are uniquely situated to learn from IPPs in the ICU. Perceived benefits include expansion of their knowledge base and fostering relationships with the interprofessional team. The unique teaching profiles of each IPP group could be leveraged to enhance IPT in the ICU.

Abstract Background:Chronic obstructive pulmonary disease (COPD) is a major global health burden, with genome-wide association studies explaining only a fraction of its heritability. Recent advancements, including large-scale, multi-ancestry whole-genome sequencing and a focus on severe, early-onset cases, offer promising avenues to identify additional COPD-related variants. Furthermore, recent studies show that adjusting for polygenic risk scores (PRS) enhances statistical power to detect rare variants, advancing efforts to understand COPD's genetic basis. Methods:We performed a whole genome sequencing association study of severe, early-onset COPD (FEV1 < 50%, age ≤ 55), FEV1 and FEV1/FVC in eight population-based studies (ARIC, CARDIA, CFS, CHS, FHS, HCHS/SOL, JHS, MESA) and seven COPD-enriched studies (COPDGene, ECLIPSE, Boston Early-Onset COPD Study, LTRC, TCGS (Poland), ICGN, SPIROMICS). We performed single-variant analyses using regenie software, applying a genome-wide significance threshold of P < 5.0 x 10-8. For rare variant set (MAF <1%) analysis, we annotated variants with loss of function or deleterious missense using WGS Annotator and prediction tools LOFTEE, SIFT, and PolyPhen2, then analyzed these variants with SKATO-ACAT method in regenie, adjusting for covariates including sex, sequencing center, and principal components of ancestry. We additionally evaluated adjusting the analyses for PRSs for lung function traits. Results: We analyzed 53,028 participants including 34,751 European, 12,508 African, 1,088 Latino American, and 674 East Asian ancestry. Across cohorts, we analyzed 5,063 severe (FEV1 < 50%) COPD cases, among whom 1,103 were early-onset (age ≤ 55). Excluding variants within 1 Mbp of known variants, single-variant analysis identified 68 novel associations (MAC ≥ 30), with 8 common associations (MAF ≥ 1%) in 6 genomic regions. Our most significant novel association for severe early-onset COPD was rs74297390 (intergenic to POM121L12, MAF = 9.6%, Beta = 0.41, P = 3.5 x 10-8). For FEV1 and FEV1/FVC ratio, variants near DKK2 and AKR1E2 were significantly associated and were replicated in an independent dataset (Shrine et al., 2019). DKK2 is an antagonist in the Wnt pathway. In a preliminary variant set analysis, CHRM3-AS1 was associated with severe early-onset COPD, GPAT with FEV1, and COL8A1I and HMCN1 with FEV1/FVC. With PRS adjustment, ST6GALNAC5 was associated with FEV1/FVC. Conclusions: In a whole genome sequencing study of lung function and severe early-onset COPD, we identified new loci for COPD-related phenotypes, including two novel loci that replicated in an independent dataset. Ongoing work involves variant set-based analyses with additional covariate adjustments, as well as PRS adjustments for binary traits.

Abstract Rationale: The club cell secretory protein (CC16), encoded by the SCGB1A1 gene, has an anti-inflammatory role in airways diseases, including asthma (Li, AJRCCM 2023; Voraphani, AJRCCM 2023). We hypothesize that additional pathway genes regulated or co-expressed with CC16 have cumulative effects on asthma severity outcomes by modulating airway inflammation and maintaining lung homeostasis. Methods: As published previously, four genes were downregulated in CC16 knockout experiments and correlated with CC16 levels: BPIFA1, SFTPD, LTF, and LYZ (Iannuzo, Front. Immunol 2023). We developed a four-gene biomarker score in 94 patients with asthma from the NHLBI-sponsored Severe Asthma Research Program (SARP3) who underwent research bronchoscopy for lower airway epithelial brushings, RNA isolation, and bulk RNA sequencing. We log-transformed the raw values of each transcript; obtained standardized residuals from regression models that included sex, age, and batch effects; and summed the standardized residuals of all four proteins to estimate a standardized sum score (Zhai, JACI Allergy 2024). Logistic regression models tested the four-gene score, three-gene score without LTF, and individual transcripts for associations with exacerbations during 12-month follow-up and zero-inflated negative binomial regression for number of exacerbations. Results: 30.85% percent of 94 patients experienced at least one exacerbation at the end of follow-up. The CC16-associated four-gene biomarker score showed protective effects on asthma exacerbation risk with a 54% percent reduction in exacerbation risk for every one-fold higher score (OR=0.46, 95% CI: 0.27-0.78, p =0.0040, Figure 1). Transcript expression of BPIFA1 (OR=0.87, 95% CI:0.66-1.16, p=0.337), SFTPD (OR=0.33, 95% CI:0.04-2.52, p=0.283), LYZ (OR=0.62, 95%CI:0.28-1.39, p=0.248), and LTF (OR=0.36, 95% CI:0.18-0.74, p=0.0053) all indicated protective directionality with respect to exacerbation risk. However, only LTF demonstrated a statistically significant association. When we excluded LTF, the remaining three-gene score showed a trend toward association with risk (OR=0.64, 95% CI:0.40-1.03, p=0.068) and was significantly associated with number of exacerbations (RR=0.49, 95% CI:0.26-0.95, p=0.034). Compared to LTF alone (OR=0.48, PPV=0.50, NPV=0.71, Sensitivity=0.14, AUC=0.65), the combined four-gene score (OR=0.46, PPV=0.60, NPV= 0.73, Sensitivity=0.21, AUC=0.68) showed improved predictive performance. Conclusions: We identified a CC16-associated transcriptomic predictive score for asthma exacerbations, with LTF showing the strongest effect. Although the other three genes showed individually weak and non-significant associations with exacerbations, the three gene score was significant for number of exacerbations.We demonstrate the potential of this transcriptomic score as a predictive biomarker for asthma severity-related outcomes. Further research investigating these genes and their interaction with other CC16-associated immune pathways could provide insight into therapeutic targets.

Abstract RATIONALE: 4G4G/4G5G SERPINE1 genotypes produce high concentrations of plasminogen activator inhibitor-1 and are associated with worse asthma outcomes. A secondary analysis of the American Lung Association (ALA) SOYA trial showed that soy isoflavones significantly reduced asthma exacerbations versus placebo among patients with 4G4G/4G5G SERPINE1 genotypes. We hypothesized that baseline characteristics predict optimal responders to soy isoflavones among this subgroup. METHODS: ALA-SOYA was a randomized controlled trial that tested the efficacy of soy isoflavones vs. placebo for reducing asthma exacerbations among adolescents and adults with symptomatic asthma. In this responder analysis among participants with 4G4G/4G5G SERPINE1 genotypes, baseline demographic and clinical characteristics were tested for effect modification of the treatment assignment (soy/placebo) on the primary outcome of annualized number of asthma exacerbations using interaction terms in negative binomial regression models, with a significance threshold of p-interaction=0.15. RESULTS: Data were available for n=168 participants. Soy reduced the annualized number of asthma exacerbations relative to placebo among patients with 4G4G/4G5G SERPINE1 genotypes (incident rate ratio (IRR)=0.37, 95% confidence interval (CI): 0.15-0.90, p=0.028). Self-reported adherence to baseline controller therapy was the only significant effect modifier of this association (interaction p=0.115), with those using inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) controller therapy at least twice weekly experiencing reductions in asthma exacerbations with soy versus placebo (IRR = 0.25, 95% CI: 0.09-0.69; p= 0.007) but not among those using ICS/LABA controller therapy less frequently (IRR = 1.33, 95% CI: 0.22-8.02; p= 0.757). CONCLUSION: Soy isoflavones reduce asthma exacerbations among patients with the 4G4G/4G5G SERPINE1 genotypes and are most effective in those with greater adherence to asthma controller therapy regimens.

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.

AbstractA diverse workforce in emergency medicine (EM) aims to improve patient care by addressing racism in health care, increasing representation in medicine, and improving the quality of training for all residents. Many EM residency programs have launched recruitment efforts to attract residents from diverse backgrounds. However, recruitment efforts only represent the first step in building a culturally responsible workforce. Trainees who are underrepresented in medicine must be welcomed into an inclusive training environment that has been thoughtfully constructed before they arrive. This type of supportive environment can be achieved by shifting away from majority‐serving ideals and building an informed infrastructure that functions to help all trainees succeed. We expand upon challenges and areas of opportunity at the individual, departmental, and institutional levels and describe common pitfalls when trying to create inclusive spaces for residents including lack of vision alignment, inadequate financial investment, and performative allyship. We also propose strategies that focus specifically on actionable changes that residency program, departmental, and institutional leadership can implement to mitigate these challenges.

ImportanceMetastatic cutaneous Crohn disease (MCD) is a rare condition for which there are currently no published diagnostic criteria. Formal MCD diagnostic criteria will expand clinical care and research by enabling future diagnostic code validation, crystallizing a more uniform disease entity for the purposes of translational research, and allowing the development of more formalized outcome measures aimed at treatment response.ObjectiveTo define a set of criteria for the diagnosis of MCD.Evidence ReviewIn this consensus statement, a panel of experts on MCD and related conditions was assembled. Their opinions were gathered regarding the clinical and histologic findings that are sufficient, necessary, and highly suggestive of MCD through serial survey. Subsequent surveys were continued until consensus was achieved. Sufficient was defined as a feature that, if noted, would enable diagnosis of MCD without any other signs, symptoms, or testing. Necessary was defined as a feature that must be present to establish a diagnosis of MCD. Highly suggestive referred to any other features that were indicative of MCD but did not qualify as sufficient or necessary to diagnose MCD.FindingsOf 24 experts invited, 19 agreed to participate, with a 79% to 100% response rate across 5 rounds conducted. Five patients were also invited to participate, but none opted to participate, citing lack of clinical expertise and time concerns. The experts were all from the US; 5 (26%) have practiced medicine for 0 to 5 years, 5 (26%) practiced for 6 to 10 years, 6 (32%) practiced for 11 to 15 years, and 3 (16%) practiced for more than 20 years. A total of 18 experts (95%) worked in an academic practice setting. There was consensus agreement that MCD could present as oral disease, genital disease, or, rarely, in another location. Consensus was achieved on 2 major and 5 minor criteria for genital/other subtypes of MCD and 5 minor criteria for oral MCD. There was consensus that, while there are some pathological findings that are highly suggestive of MCD, histologic criteria are not necessary for diagnosis.Conclusions and RelevanceA panel of experts reached consensus on the diagnostic criteria for MCD described in this study. These criteria include major and minor clinical criteria, along with histopathological criteria for the diagnosis of genital and oral MCD. This consensus is a crucial step in the diagnosis of and future treatment development for MCD, a rare and clinically understudied condition.

AbstractPurposeWhile several artificial intelligence (AI)‐assisted medical imaging applications are reported in the recent orthopaedic literature, comparison of the clinical efficacy and utility of these applications is currently lacking. The aim of this systematic review is to evaluate the effectiveness and reliability of AI applications in orthopaedic imaging, focusing on their impact on diagnostic accuracy, image segmentation and operational efficiency across various imaging modalities.MethodsBased on the PRISMA guidelines, a comprehensive literature search of PubMed, Cochrane and Scopus databases was performed, using combinations of keywords and MeSH descriptors ('AI', 'ML', 'deep learning', 'orthopaedic surgery' and 'imaging') from inception to March 2024. Included were studies published between September 2018 and February 2024, which evaluated machine learning (ML) model effectiveness in improving orthopaedic imaging. Studies with insufficient data regarding the output variable used to assess the reliability of the ML model, those applying deterministic algorithms, unrelated topics, protocol studies, and other systematic reviews were excluded from the final synthesis. The Joanna Briggs Institute (JBI) Critical Appraisal tool and the Risk Of Bias In Non‐randomised Studies‐of Interventions (ROBINS‐I) tool were applied for the assessment of bias among the included studies.ResultsThe 53 included studies reported the use of 11.990.643 images from several diagnostic instruments. A total of 39 studies reported details in terms of the Dice Similarity Coefficient (DSC), while both accuracy and sensitivity were documented across 15 studies. Precision was reported by 14, specificity by nine, and the F1 score by four of the included studies. Three studies applied the area under the curve (AUC) method to evaluate ML model performance. Among the studies included in the final synthesis, Convolutional Neural Networks (CNN) emerged as the most frequently applied category of ML models, present in 17 studies (32%).ConclusionThe systematic review highlights the diverse application of AI in orthopaedic imaging, demonstrating the capability of various machine learning models in accurately segmenting and analysing orthopaedic images. The results indicate that AI models achieve high performance metrics across different imaging modalities. However, the current body of literature lacks comprehensive statistical analysis and randomized controlled trials, underscoring the need for further research to validate these findings in clinical settings.Level of evidenceSystematic Review; Level of evidence IV.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the GRADE approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the Grading of Recommendations, Assessment, Development and Evaluation approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.