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* Context.--Recent data support that low-risk submucosally invasive (pT1) colonic adenocarcinomas (ie, completely resected tumors that lack high-grade morphology, tumor budding, and lymphovascular invasion) are considered cured via endoscopic resection, provided that the submucosal invasion is less than 1000 [micro]m. Hence, the pathologists' assessment of depth of submucosal invasion may guide further management (ie, surveillance versus colectomy). Objective.--To assess interobserver concordance among gastrointestinal pathologists in measuring submucosal depth of invasion in colonic endoscopic resections. Design.--Six gastrointestinal pathologists from 5 academic centers independently measured the greatest depth of submucosal invasion in micrometers on 52 hematoxylineosin-stained slides from colonic endoscopic specimens with pT1 adenocarcinomas, per published guidelines (round 1 scoring). Two separate measurements (round 2 scoring) were subsequently performed by each pathologist following a consensus meeting, (1) from the surface of the lesion and (2) from the muscularis mucosae, and pathologists were asked to choose their (3) 'real-life (best)' assessment between the first 2 measurements. Interobserver agreement was assessed by the intraclass correlation coefficient (ICC) and Cohen [kappa] statistics. Results.--Round 1 had poor ICC (0.43; 95% CI, 0.31-0.56). Round 2 agreement was good when measuring from the surface (ICC = 0.83; 95% CI, 0.76-0.88) but moderate (ICC = 0.59; 95% CI, 0.47-0.70) when measuring from the muscularis mucosae and became poor (ICC = 0.49; 95% CI, 0.36-0.61) for the best-assessment measurement. Conclusions.--Our findings indicate that clearer and reproducible guidelines are needed if clinical colleagues are to base important management decisions on pathologists' estimate of the depth of submucosal invasion in colonic endoscopic resections. doi: 10.5858/arpa.2021-0598-OA, Widespread screening colonoscopy procedures and advances in definitive endoscopic therapy call for precise and reproducible criteria for the evaluation of superficially invasive colorectal adenocarcinoma (CRC) in endoscopic resections. Submucosa-invasive CRC [...]

BackgroundMinority groups of African descent experience disproportionately greater asthma morbidity compared with other racial groups, suggesting that genetic variation from a common ancestry could influence exacerbation risk.ObjectiveWe evaluated clinical trial measures in the context of self-reported race and genetic ancestry to identify risk factors for asthma exacerbations.MethodsOne thousand eight hundred forty multiethnic subjects from 12 Asthma Clinical Research Network and AsthmaNet trials were analyzed for incident asthma exacerbations with Poisson regression models that included clinical measures, self-reported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n = 760).ResultsTwenty-four percent of 1840 subjects self-identified as black. Black and white subjects had common risk factors for exacerbations, including a history of 2 or more exacerbations in the previous year and FEV1 percent predicted values, whereas chronic sinusitis, allergic rhinitis, and gastroesophageal reflux disease were only associated with increased exacerbation risk in black subjects. In the combined multiethnic cohort, neither race (P = .30) nor percentage of genetic African ancestry as a continuous variable associated with exacerbation risk (adjusted rate ratio [RR], 1.26 [95% CI, 0.94-1.70; P = .13]; RR per 1-SD change [32% ancestry], 0.97 [95% CI, 0.78-1.19; P = .74]). However, in 161 black subjects with genetic data, those with African ancestry greater than the median (≥82%) had a significantly greater risk of exacerbation (RR, 3.06 [95% CI, 1.09-8.6; P = .03]).ConclusionBlack subjects have unique risk factors for asthma exacerbations, of which global African genetic ancestry had the strongest effect.

BACKGROUND:In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS:In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (

Precision medicine is expected to impact the care of people with asthma, given its high disease prevalence, heterogeneity of pathophysiologic mechanisms, and consequent clinical phenotypes. A novel phenotype-stratified clinical trial conducted by the NHLBI AsthmaNet Consortium, titled Steroids in Eosinophil Negative Asthma (SIENA), was a randomized, multicenter, clinical trial that prospectively stratified individuals according to their baseline level of sputum inflammation during a screening period. Two phenotypic strata were assigned based on an a priori defined extent of sputum eosinophilia (Eos Low versus Eos High). This article describes: the scientific premise for the trial design, including assumptions used for power calculations; modifications to the analysis plan implemented after the trial started due to a higher than expected prevalence of one phenotypic stratum which impacted the ability to accrue sufficient subjects within the planned budget and study period; investigator alternatives to address the strata imbalance weighing scientific impact and study feasibility; and the final modified SIENA study design and analysis plan. SIENA was successfully completed in a manner that maintained meaningful outcomes. We conclude with recommendations for incorporation of pre-specified contingency plans into phenotype-directed protocols, to address the potential for differences in observed compared to estimated prevalence of different phenotypes in a study population. These approaches can be applied to precision medicine trials for the future.

BackgroundPerturbations to the composition and function of bronchial bacterial communities appear to contribute to the pathophysiology of asthma. Unraveling the nature and mechanisms of these complex associations will require large longitudinal studies, for which bronchoscopy is poorly suited. Studies of samples obtained by sputum induction and nasopharyngeal brushing or lavage have also reported asthma-associated microbiota characteristics. It remains unknown, however, whether the microbiota detected in these less-invasive sample types reflect the composition of bronchial microbiota in asthma.ResultsBacterial microbiota in paired protected bronchial brushings (BB; n = 45), induced sputum (IS; n = 45), oral wash (OW; n = 45), and nasal brushings (NB; n = 27) from adults with mild atopic asthma (AA), atopy without asthma (ANA), and healthy controls (HC) were profiled using 16S rRNA gene sequencing. Though microbiota composition varied with sample type (p

BackgroundThe use of inflammatory biomarkers to delineate the type of lung inflammation present in asthmatic subjects is increasingly common. However, the effect of obesity on these markers is unknown.ObjectivesWe aimed to determine the effect of obesity on conventional markers of inflammation in asthmatic subjects.MethodsWe performed secondary analysis of data from 652 subjects previously enrolled in 2 Asthma Clinical Research Network trials. We performed linear correlations between biomarkers and logistic regression analysis to determine the predictive value of IgE levels, blood eosinophil counts, and fraction of exhaled nitric oxide values in relationship to sputum eosinophil counts (>2%), as well as to determine whether cut points existed that would maximize the sensitivity and specificity for predicting sputum eosinophilia in the 3 weight groups.ResultsOverall, statistically significant but relatively weak correlations were observed among all 4 markers of inflammation. Within obese subjects, the only significant correlation found was between IgE levels and blood eosinophil counts (r = 0.33, P

ImportanceIn asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.ObjectiveTo evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels.Design, setting, and participantsThe VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized.InterventionsOral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained.Main outcomes and measuresThe primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care).ResultsTreatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]).Conclusions and relevanceVitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.Trial registrationclinicaltrials.gov Identifier: NCT01248065.

ContextNo consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.ObjectiveTo determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma.Design, setting, and participantsA randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.InterventionsFor physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.Main outcome measureThe primary outcome was time to treatment failure.ResultsThere were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).ConclusionAmong adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure.Trial registrationclinicaltrials.gov Identifier: NCT00495157.

Objectives Endoscopic endonasal anterior skull base surgery has expanding use in the pediatric population, but the anatomy of pediatric patients can lead to limitations. This study aims to characterize the important anatomical implications of the pediatric skull base using computed tomography (CT) scans. Design This study is designed as retrospective analysis. Setting The study setting comprises of tertiary academic medical center. Participants In total, 506 patients aged 0 to 18 who had undergone maxillofacial and or head CTs between 2009 to 2016 were involved. Methods Measurements included piriform aperture width, nare to sella distance (NSD), sphenoid pneumatization, olfactory fossa depth, lateral lamella cribriform plate angles, and intercarotid distances (ICD) at the superior clivus and cavernous sinus. These patients were then subdivided into three age groups adjusting for sex. Analysis of covariance (ANCOVA) models were fit comparing between all age groups and by sex. Results Piriform aperture width, NSD, sphenoid sinus pneumatization as measured using lateral aeration and anterior sellar wall thickness, olfactory fossa depth, and ICD at the cavernous sinus were significantly different among all age groups (p <0.0001). Our results show that mean piriform aperture width increased with each age group. The mean olfactory fossa depth also had consistent age dependent growth. In addition, ICD at the cavernous sinus showed age dependent changes. When comparing by sexes, females consistently showed smaller measurements. Conclusion The process of skull base development is age and sex dependent. During preoperative evaluation of pediatric patients for skull base surgery piriform aperture width, sphenoid pneumatization in both the anterior posterior and lateral directions, and ICD at the cavernous sinus should be carefully reviewed. [ABSTRACT FROM AUTHOR]

Background: Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype. Methodology and Principal Findings: In a cohort of clinical trial participants (n = 250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m²) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (FENO) and airway hyperresponsiveness (methacholine PC20) but were similar with regard to measures of lung function (FEV1 (%) and FEV1/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasone Conclusions and Significance: Obesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to examine students' perceptions of pass/fail scoring for Step 1, particularly when applying to competitive specialties. This study also investigated whether this transition increased anxiety among medical students and elicited student perspectives on the most critical components of residency applications., Introduction: The United States Medical Licensing Exam (USMLE) Step 1 Board Exam transitioned from a traditional numeric score to pass/fail for exams taken on or after January 26, 2022. One justification for this change, according to a statement from USMLE, was to ease the transition between undergraduate and graduate medical education. Although many factors are considered when selecting candidates to interview for residency, Step 1 scores were historically used as an important metric. Few studies specifically evaluated medical student's attitudes toward the change in Step 1 grading., Methods: An online survey was distributed to Penn State College of Medicine medical students in the 2024 to 2027 classes. Statistical analysis was conducted on responses to research plans, attitudes regarding Step 1 pass/fail, match rates, and importance of application components., Results: There was a 21.3% response rate (127/596) to the survey with 30.7% pursuing a competitive specialty. Students applying into competitive specialties felt their chances of matching changed significantly compared to students applying to other specialties (either increased (25.6% vs 10.2%, P  < .001), or decreased (28.2% vs10.3%, P  < .001). Majority of students (73.2%) agreed with the decision to make Step 1 pass/fail, however, students reported increased anxiety surrounding Step 2 scores. There was a significant association between which aspects students believed were most important for matching (letters of recommendation and performance on Acting Internships) and those they believed program directors would weigh heaviest ( P  < .001)., Conclusion: Medical students report increased anxiety with Step 2 after Step 1 became pass/fail, although students overwhelmingly agreed with this change. To address this, medical schools should offer further guidance and resources to students, focusing on mentorship and methods to optimize residency applications for their chosen specialties., Competing Interests: Dr. Karen Y. Choi is a consultant for Cardinal Health; this position does not conflict with this study. No funding organization had any role in survey design, implementation, or analysis., (© The Author(s) 2024.)