Tobacco smoking is associated with combined pulmonary fibrosis and emphysema and worse outcomes in interstitial lung disease.

Tobacco smoking is an established cause of pulmonary disease whose contribution to interstitial lung disease (ILD) is incompletely characterized. We hypothesized that compared with nonsmokers, subjects who smoked tobacco would differ in their clinical phenotype and have greater mortality. We performed a retrospective cohort study of tobacco smoking in ILD. We evaluated demographic and clinical characteristics, time to clinically meaningful lung function decline (LFD), and mortality in patients stratified by tobacco smoking status (ever vs. never) within a tertiary center ILD registry (2006-2021) and replicated mortality outcomes across four nontertiary medical centers. Data were analyzed by two-sided t tests, Poisson generalized linear models, and Cox proportional hazard models adjusted for age, sex, forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), ILD subtype, antifibrotic therapy, and hospital center. Of 1,163 study participants, 651 were tobacco smokers. Smokers were more likely to be older, male, have idiopathic pulmonary fibrosis (IPF), coronary artery disease, CT honeycombing and emphysema, higher FVC, and lower DLCO than nonsmokers (P < 0.01). Time to LFD in smokers was shorter (19.7 ± 20 mo vs. 24.8 ± 29 mo; P = 0.038) and survival time was decreased [10.75 (10.08-11.50) yr vs. 20 (18.67-21.25) yr; adjusted mortality HR = 1.50, 95%CI 1.17-1.92; P < 0.0001] compared with nonsmokers. Smokers had 12% greater odds of death for every additional 10 pack yr of smoking (P < 0.0001). Mortality outcomes remained consistent in the nontertiary cohort (HR = 1.51, 95%CI = 1.03-2.23; P = 0.036). Tobacco smokers with ILD have a distinct clinical phenotype strongly associated with the syndrome of combined PF and emphysema, shorter time to LFD, and decreased survival. Smoking prevention may improve ILD outcomes.NEW & NOTEWORTHY Smoking in ILD is associated with combined pulmonary fibrosis and emphysema and worse clinical outcomes.

Anti-Granulocyte-Macrophage Colony-Stimulating Factor Monoclonal Antibody Gimsilumab for COVID-19 Pneumonia: A Randomized, Double-Blind, Placebo-controlled Trial.

Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).

Randomized Phase 3 Trial of Ruxolitinib for COVID-19-Associated Acute Respiratory Distress Syndrome.

OBJECTIVES: Evaluate the safety and efficacy of the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib in COVID-19-associated acute respiratory distress syndrome requiring mechanical ventilation. DESIGN: Phase 3 randomized, double-blind, placebo-controlled trial Ruxolitinib in Participants With COVID-19-Associated Acute Respiratory Distress Syndrome Who Require Mechanical Ventilation (RUXCOVID-DEVENT; NCT04377620). SETTING: Hospitals and community-based private or group practices in the United States (29 sites) and Russia (4 sites). PATIENTS: Eligible patients were greater than or equal to 12 years old, hospitalized with severe acute respiratory syndrome coronavirus 2 infection, and mechanically ventilated with a Pa o2 /F io2 of less than or equal to 300 mm Hg within 6 hours of randomization. INTERVENTIONS: Patients were randomized 2:2:1 to receive twice-daily ruxolitinib 15 mg, ruxolitinib 5 mg, or placebo, each plus standard therapy. MEASUREMENTS AND MAIN RESULTS: The primary endpoint, 28-day mortality, was tested for each ruxolitinib group versus placebo using a mixed-effects logistic regression model and one-tailed significance test (significance threshold: p < 0.025); no type 1 error was allocated to secondary endpoints. Between May 24, 2020 and December 15, 2020, 211 patients (age range, 24-87 yr) were randomized (ruxolitinib 15/5 mg, n = 77/87; placebo, n = 47). Acute respiratory distress syndrome was categorized as severe in 27% of patients (58/211) at randomization; 90% (190/211) received concomitant steroids. Day-28 mortality was 51% (39/77; 95% CI, 39-62%) for ruxolitinib 15 mg, 53% (45/85; 95% CI, 42-64%) for ruxolitinib 5 mg, and 70% (33/47; 95% CI, 55-83%) for placebo. Neither ruxolitinib 15 mg (odds ratio, 0.46 [95% CI, 0.201-1.028]; one-sided p = 0.029) nor 5 mg (odds ratio, 0.42 [95% CI, 0.171-1.023]; one-sided p = 0.028) significantly reduced 28-day mortality versus placebo. Numerical improvements with ruxolitinib 15 mg versus placebo were observed in secondary outcomes including ventilator-, ICU-, and vasopressor-free days. Rates of overall and serious treatment-emergent adverse events were similar across treatments. CONCLUSIONS: The observed reduction in 28-day mortality rate between ruxolitinib and placebo in mechanically ventilated patients with COVID-19-associated acute respiratory distress syndrome was not statistically significant; however, the trial was underpowered owing to early termination.

Prognosticating Outcomes in Interstitial Lung Disease by Mediastinal Lymph Node Assessment. An Observational Cohort Study with Independent Validation.

RATIONALE: Mediastinal lymph node (MLN) enlargement on chest computed tomography (CT) is prevalent in patients with interstitial lung disease (ILD) and may reflect immunologic activation and subsequent cytokine-mediated immune cell trafficking. OBJECTIVES: We aimed to determine whether MLN enlargement on chest CT predicts clinical outcomes and circulating cytokine levels in ILD. METHODS: MLN measurements were obtained from chest CT scans of patients with ILD at baseline evaluation over a 10-year period. Patients with sarcoidosis and drug toxicity-related ILD were excluded. MLN diameter and location were assessed. Plasma cytokine levels were analyzed in a subset of patients. The primary outcome was transplant-free survival (TFS). Secondary outcomes included all-cause and respiratory hospitalizations, lung function, and plasma cytokine concentrations. Cox regression was used to assess mortality risk. Outcomes were assessed in three independent ILD cohorts. MEASUREMENTS AND MAIN RESULTS: Chest CT scans were assessed in 1,094 patients (mean age, 64 yr; 52% male). MLN enlargement (≥10 mm) was present in 66% (n = 726) and strongly predicted TFS (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.12-2.10; P = 0.008) and risk of all-cause and respiratory hospitalizations (internal rate of return [IRR], 1.52; 95% CI, 1.17-1.98; P = 0.002; and IRR, 1.71; 95% CI, 1.15-2.53; P = 0.008, respectively) when compared with subjects with MLN <10 mm. Patients with MLN enlargement had lower lung function and decreased plasma concentrations of soluble CD40L (376 pg/ml vs. 505 pg/ml, P = 0.001) compared with those without MLN enlargement. Plasma IL-10 concentration >45 pg/ml predicted mortality (HR, 4.21; 95% CI, 1.21-14.68; P = 0.024). Independent analysis of external datasets confirmed these findings. CONCLUSIONS: MLN enlargement predicts TFS and hospitalization risk in ILD and is associated with decreased levels of a key circulating cytokine, soluble CD40L. Incorporating MLN and cytokine findings into current prediction models might improve ILD prognostication.

African-American race and mortality in interstitial lung disease: a multicentre propensity-matched analysis.

We studied whether African-American race is associated with younger age and decreased survival time at diagnosis of interstitial lung disease (ILD).We performed a multicentre, propensity score-matched analysis of patients with an ILD diagnosis followed at five US hospitals between 2006 and 2016. African-Americans were matched with patients of other races based on a time-dependent propensity score calculated from multiple patient, physiological, diagnostic and hospital characteristics. Multivariable logistic regression models were used. All-cause mortality and hospitalisations were compared between race-stratified patient cohorts with ILD, and sensitivity analyses were performed.The study included 1640 patients with ILD, 13% of whom were African-American, followed over 5041 person-years. When compared with patients of other races, African-Americans with ILD were younger at diagnosis (56 years versus 67 years), but in the propensity-matched analyses had greater survival (hazard ratio 0.46, 95% CI 0.28-0.77; p=0.003) despite similar risk of respiratory hospitalisations (relative risk 1.04, 95% CI 0.83-1.31; p=0.709), and similar GAP-ILD (gender-age-physiology-ILD) scores at study entry. Sensitivity analyses in a separate cohort of 9503 patients with code-based ILD diagnosis demonstrated a similar association of baseline demographic characteristics with all-cause mortality.We conclude that African-Americans demonstrate a unique phenotype associated with younger age at ILD diagnosis and perhaps longer survival time.

Predicting Pulmonary Function from Phone Sensors.

INTRODUCTION: Smartphones are ubiquitous, but it is unknown what physiological functions can be monitored at clinical quality. Pulmonary function is a standard measure of health status for cardiopulmonary patients. We have shown phone sensors can accurately measure walking patterns. Here we show that improved classification models can accurately predict pulmonary function, with sole inputs being motion sensors from carried phones. SUBJECTS AND METHODS: Twenty-five cardiopulmonary patients performed 6-minute walk tests in pulmonary rehabilitation at a regional hospital. They carried smartphones running custom software recording phone motion. Each patient's pulmonary function was measured by spirometry. A universal model, based on support vector machine, then computed the category of function with input from signal processing features and patient demographic features. RESULTS: All but a few of every 10-second interval for every patient was correctly predicted. The trained model perfectly computed the GOLD (Global Initiative for Chronic Obstructive Lung Disease) level 1/2/3, which is a standard classification of pulmonary function. Each level was determined to have a characteristic motion, which could be recognized from the sensor features. In addition, longitudinal changes were detected for 10 patients with multiple walk tests, except for cases with clinical instability. CONCLUSIONS: These results are encouraging toward clinical validation of passive monitors running continuously in the background, for patients in homes during daily activities. Initial testing indicates the same high accuracy as with active monitors, for patients in hospitals during walk tests. We expect patients can simply carry their phones during everyday living, while models support automatic prediction of pulmonary function for health monitoring.

Assessment of Awake Prone Positioning in Hospitalized Adults With COVID-19: A Nonrandomized Controlled Trial.

Importance: Awake prone positioning may improve hypoxemia among patients with COVID-19, but whether it is associated with improved clinical outcomes remains unknown. Objective: To determine whether the recommendation of awake prone positioning is associated with improved outcomes among patients with COVID-19-related hypoxemia who have not received mechanical ventilation. Design, Setting, and Participants: This pragmatic nonrandomized controlled trial was conducted at 2 academic medical centers (Vanderbilt University Medical Center and NorthShore University HealthSystem) during the COVID-19 pandemic. A total of 501 adult patients with COVID-19-associated hypoxemia who had not received mechanical ventilation were enrolled from May 13 to December 11, 2020. Interventions: Patients were assigned 1:1 to receive either the practitioner-recommended awake prone positioning intervention (intervention group) or usual care (usual care group). Main Outcomes and Measures: Primary outcome analyses were performed using a bayesian proportional odds model with covariate adjustment for clinical severity ranking based on the World Health Organization ordinal outcome scale, which was modified to highlight the worst level of hypoxemia on study day 5. Results: A total of 501 patients (mean [SD] age, 61.0 [15.3] years; 284 [56.7%] were male; and most [417 (83.2%)] were self-reported non-Hispanic or non-Latinx) were included. Baseline severity was comparable between the intervention vs usual care groups, with 170 patients (65.9%) vs 162 patients (66.7%) receiving oxygen via standard low-flow nasal cannula, 71 patients (27.5%) vs 62 patients (25.5%) receiving oxygen via high-flow nasal cannula, and 16 patients (6.2%) vs 19 patients (7.8%) receiving noninvasive positive-pressure ventilation. Nursing observations estimated that patients in the intervention group spent a median of 4.2 hours (IQR, 1.8-6.7 hours) in the prone position per day compared with 0 hours (IQR, 0-0.7 hours) per day in the usual care group. On study day 5, the bayesian posterior probability of the intervention group having worse outcomes than the usual care group on the modified World Health Organization ordinal outcome scale was 0.998 (posterior median adjusted odds ratio [aOR], 1.63; 95% credibility interval [CrI], 1.16-2.31). However, on study days 14 and 28, the posterior probabilities of harm were 0.874 (aOR, 1.29; 95% CrI, 0.84-1.99) and 0.673 (aOR, 1.12; 95% CrI, 0.67-1.86), respectively. Exploratory outcomes (progression to mechanical ventilation, length of stay, and 28-day mortality) did not differ between groups. Conclusions and Relevance: In this nonrandomized controlled trial, prone positioning offered no observed clinical benefit among patients with COVID-19-associated hypoxemia who had not received mechanical ventilation. Moreover, there was substantial evidence of worsened clinical outcomes at study day 5 among patients recommended to receive the awake prone positioning intervention, suggesting potential harm. Trial Registration: ClinicalTrials.gov Identifier: NCT04359797.

Nuclear import of serum response factor in airway smooth muscle.

We have previously shown that the transcription-promoting activity of serum response factor (SRF) is partially regulated by its extranuclear redistribution. In this study, we examined the cellular mechanisms that facilitate SRF nuclear entry in canine tracheal smooth muscle cells. We used in vitro pull-down assays to determine which karyopherin proteins bound SRF and found that SRF binds KPNA1 and KPNB1 through its nuclear localization sequence. Immunoprecipitation studies also demonstrated direct SRF-KPNA1 interaction in HEK293 cells. Import assays demonstrated that KPNA1 and KPNB1 together were sufficient to mediate rapid nuclear import of SRF-GFP. Our studies also suggest that SRF is able to gain nuclear entry through an auxiliary, nuclear localization sequence-independent mechanism.

Association of antinuclear antibody seropositivity with inhaled environmental exposures in patients with interstitial lung disease.

BACKGROUND: Interstitial lung diseases (ILDs) are diffuse parenchymal lung disorders that cause substantial morbidity and mortality. In patients with ILD, elevated antinuclear antibody (ANA) titres may be a sign of an autoimmune process. Inhalational exposures contribute to ILD pathogenesis and affect prognosis and may trigger autoimmune disease. The association of inhalational exposures with ANA seropositivity in ILD patients is unknown. METHODS: This was a retrospective cohort study of adult ILD patients from five centres in the United States. Exposures to tobacco, inhaled organic antigens and inhaled inorganic particles were extracted from medical records. A multivariable logistic regression model was used to analyse the effects of confounders including age, ILD diagnosis, gender and exposure type on ANA seropositivity. RESULTS: Among 1265 patients with ILD, there were more ANA-seropositive (58.6%, n=741) than ANA-seronegative patients (41.4%, n=524). ANA-seropositive patients had lower total lung capacity (69% versus 75%, p<0.001) and forced vital capacity (64% versus 70%, p<0.001) than patients who were ANA-seronegative. Among patients with tobacco exposure, 61.4% (n=449) were ANA-positive compared to 54.7% (n=292) of those without tobacco exposure. In multivariable analysis, tobacco exposure remained independently associated with increased ANA seropositivity (OR 1.38, 95% CI 1.12-1.71). This significant difference was similarly demonstrated among patients with and without a history of inorganic exposures (OR 1.52, 95% CI 1.12-2.07). CONCLUSION: Patients with ILD and inhalational exposure had significantly higher prevalence of ANA-seropositivity than those without reported exposures across ILD diagnoses. Environmental and occupational exposures should be systematically reviewed in patients with ILD, particularly those with ANA-seropositivity.

CPAP Adherence, Mortality, and Progression-Free Survival in Interstitial Lung Disease and OSA.

BACKGROUND: OSA, a common comorbidity in interstitial lung disease (ILD), could contribute to a worsened course if untreated. It is unclear if adherence to CPAP therapy improves outcomes. RESEARCH QUESTION: Does adherence to CPAP therapy improve outcomes in patients with concurrent interstitial lung disease and OSA? STUDY DESIGN AND METHODS: We conducted a 10-year retrospective observational multicenter cohort study, assessing adult patients with ILD who had undergone polysomnography. Subjects were categorized based on OSA severity into no/mild OSA (apnea-hypopnea index score < 15) or moderate/severe OSA (apnea-hypopnea index score ≥ 15). All subjects prescribed and adherent to CPAP were deemed to have treated OSA. Cox regression models were used to examine the association of OSA severity and CPAP adherence with all-cause mortality risk and progression-free survival (PFS). RESULTS: Of 160 subjects that met inclusion criteria, 131 had OSA and were prescribed CPAP. Sixty-six patients (41%) had no/mild untreated OSA, 51 (32%) had moderate/severe untreated OSA, and 43 (27%) had treated OSA. Subjects with no/mild untreated OSA did not differ from those with moderate/severe untreated OSA in mean survival time (127 ± 56 vs 138 ± 93 months, respectively; P = .61) and crude mortality rate (2.9 per 100 person-years vs 2.9 per 100 person-years, respectively; P = .60). Adherence to CPAP was not associated with improvement in all-cause mortality risk (hazard ratio [HR], 1.1; 95% CI, 0.4-2.9; P = .79) or PFS (HR, 0.9; 95% CI, 0.5-1.5; P = .66) compared with those that were nonadherent or untreated. Among subjects requiring supplemental oxygen, those adherent to CPAP had improved PFS (HR, 0.3; 95% CI, 0.1-0.9; P = .03) compared with nonadherent or untreated subjects. INTERPRETATION: Neither OSA severity nor adherence to CPAP was associated with improved outcomes in patients with ILD except those requiring supplemental oxygen.

Computed Tomography Honeycombing Identifies a Progressive Fibrotic Phenotype with Increased Mortality across Diverse Interstitial Lung Diseases.

Rationale: Honeycombing on chest computed tomography (CT) has been described in diverse forms of interstitial lung disease (ILD); however, its prevalence and association with mortality across the spectrum of ILD remains unclear. Objective: To determine the prevalence and prognostic value of CT honeycombing and characterize associated mortality patterns across diverse ILD subtypes in a multicenter cohort. Methods: This was an observational cohort study of adult participants with multidisciplinary or adjudicated ILD diagnosis and documentation of chest CT imaging at index diagnosis across five U.S. hospitals (one tertiary and four nontertiary medical centers). Participants were stratified based on presence or absence of CT honeycombing. Vital status was determined from review of medical records and social security death index. Transplant-free survival was analyzed using univariate and multivariable Cox regression. Results: The sample comprised 1,330 participants (mean age, 66.8 yr; 50% men) with 4,831 person-years of follow-up. The prevalences of CT honeycombing were 42.0%, 41.9%, 37.6%, and 28.6% in chronic hypersensitivity pneumonitis, connective tissue disease-related ILD (CTD-ILD), idiopathic pulmonary fibrosis (IPF), and unclassifiable/other ILDs, respectively. Among those with CT honeycombing, cumulative mortality hazards were similar across ILD subtypes, except for CTD-ILD, which had a lower mortality hazard. Overall, the mean survival time was shorter among those with CT honeycombing (107 mo; 95% confidence interval [CI], 92-122 mo) than those without CT honeycombing (161 mo; 95% CI, 147-174 mo). CT honeycombing was associated with an increased mortality rate (hazard ratio, 1.72; 95% CI, 1.38-2.14) even after adjustment for center, sex, age, forced vital capacity, diffusing capacity, ILD subtype, and use of immunosuppressive therapy (hazard ratio, 1.62; 95% CI, 1.29-2.02). CT honeycombing was associated with an increased mortality rate within non-IPF ILD subgroups (chronic hypersensitivity pneumonitis, CTD-ILD, and unclassifiable/other ILD). In IPF, however, mortality rates were similar between those with and without CT honeycombing. Conclusions: CT honeycombing is prevalent in diverse forms of ILD and uniquely identifies a progressive fibrotic ILD phenotype with a high mortality rate similar to IPF. CT honeycombing did not confer additional risk in IPF, which is already known to be a progressive fibrotic ILD phenotype regardless of the presence of CT honeycombing.

Impact of a Video-Based Interactive Workshop on Unprofessional Behaviors Among Internal Medicine Residents.

BACKGROUND: Unprofessional behaviors undermine the hospital learning environment and the quality of patient care. OBJECTIVE: To assess the impact of an interactive workshop on the perceptions of and self-reported participation in unprofessional behaviors. METHODS: We conducted a pre-post survey study at 3 internal medicine residency programs. For the workshop we identified unprofessional behaviors related to on-call etiquette: "blocking" an admission, disparaging a colleague, and misrepresenting a test as urgent. Formal debriefing tools were utilized to guide the discussion. We fielded an internally developed 20-item survey on perception and participation in unprofessional behaviors prior to the workshop. An online "booster" quiz was delivered at 4 months postworkshop, and the 20-item survey was repeated at 9 months postworkshop. Results were compared to a previously published control from the same institutions, which showed that perceptions of unprofessional behavior did not change and participation in the behaviors worsened over the internship. RESULTS: Of 237 eligible residents, 181 (76%) completed both pre- and postsurvey. Residents perceived blocking an admission and the misrepresentation of a test as urgent to be more unprofessional at a 9-month follow-up (2.0 versus 1.74 and 2.63 versus 2.28, respectively; P < .05), with no change in perception for disparaging a colleague. Participation in unprofessional behaviors did not decrease after the workshop, with the exception of misrepresenting a test as urgent (61% versus 50%, P = .019). CONCLUSIONS: The results of this multi-site study indicate that an interactive workshop can change perception and may lower participation in some unprofessional behaviors.

Classification Models for Pulmonary Function using Motion Analysis from Phone Sensors.

Smartphones are ubiquitous, but it is unknown what physiological functions can be monitored at clinical quality. Pulmonary function is a standard measure of health status for cardiopulmonary patients. We have shown phone sensors can accurately measure walking patterns. Here we show that improved classification models can accurately measure pulmonary function, with sole inputs being sensor data from carried phones. Twenty-four cardiopulmonary patients performed six minute walk tests in pulmonary rehabilitation at a regional hospital. They carried smartphones running custom software recording phone motion. For every patient, every ten-second interval was correctly computed. The trained model perfectly computed the GOLD level 1/2/3, which is a standard categorization of pulmonary function as measured by spirometry. These results are encouraging towards field trials with passive monitors always running in the background. We expect patients can simply carry their phones during daily living, while supporting automatic computation ofpulmonary function for health monitoring.

Outpatient Advance Care Planning Internal Medicine Resident Curriculum: Valuing Our Patients' Wishes.

BACKGROUND: Although many studies have illustrated the discomfort that resident physicians feel when discussing end-of-life (EOL) issues with their patients, fewer studies have addressed interventions to directly increase medical resident proficiency and comfort in conducting these discussions and for translating these beliefs into a formal advance care plan. OBJECTIVES: We report on an innovative curriculum conducted at The University of Chicago (NorthShore) internal medicine residency to improve residents' proficiency and comfort in leading outpatient advance care planning (ACP) discussions. METHODS: Four educational components were executed. First, residents completed an on-line module introducing ACP and guiding residents to complete their own ACP. Second, residents attended a didactic "How To" lecture given by physicians with expertise in ACP that emphasized ACP communication tools and a video demonstration. Third, residents completed a video-recorded simulation-based ACP discussion with a standardized patient. Finally, residents conducted an ACP outpatient encounter with one of their continuity clinic patients. Expert preceptors directly observed, evaluated, and provided feedback to residents during both patient encounters. Residents were surveyed before and immediately after the curriculum using a nine-variable questionnaire, which assessed the resident's training and comfort with ACP. RESULTS: Sixteen second year residents completed the curriculum and surveys. Precurriculum and post-curriculum mean change on a Likert scale of 1 (uncomfortable) to 5 (very comfortable) was compared using paired t-tests. Results demonstrated statistically significant improvements in the following comfort level variables: eliciting understanding of health and prognosis (pre 3.63 vs. post 4.38, p = 0.035), discussing EOL care based on patient values (pre 3.50 vs. post 4.38, p = 0.008), specifically discussing EOL care based on patient values in the outpatient setting (pre 2.75 vs. post 4.31, p = 0.001) and initiating an advance directive and medical power of attorney (pre 2.56 vs. post 4.19, p < 0.001). CONCLUSION: A multimodality curriculum including self-directed learning, lectures, and practice with simulated and actual outpatients with active reflection and feedback is effective in improving resident comfort level and formal training in ACP. Further research is needed to understand whether these interventions will translate into an increased frequency of discussions with patients about ACP after residency training.

What evidence implicates airway smooth muscle in the cause of BHR?

Bronchial hyperresponsiveness (BHR), the occurrence of excessive bronchoconstriction in response to relatively small constrictor stimuli, is a cardinal feature of asthma. Here, we consider the role that airway smooth muscle might play in the generation of BHR. The weight of evidence suggests that smooth muscle isolated from asthmatic tissues exhibits normal sensitivity to constrictor agonists when studied during isometric contraction, but the increased muscle mass within asthmatic airways might generate more total force than the lesser amount of muscle found in normal bronchi. Another salient difference between asthmatic and normal individuals lies in the effect of deep inhalation (DI) on bronchoconstriction. DI often substantially reverses induced bronchoconstriction in normals, while it often has much less effect on spontaneous or induced bronchoconstriction in asthmatics. It has been proposed that abnormal dynamic aspects of airway smooth muscle contraction velocity of contraction or plasticity- elasticity balance might underlie the abnormal DI response in asthma. We suggest a speculative model in which abnormally long actin filaments might account for abnormally increased elasticity of contracted airway smooth muscle.

Promoting professionalism via a video-based educational workshop for academic hospitalists and housestaff.

BACKGROUND: Unprofessional behavior can compromise care and detract from the hospital learning environment. Discrepancy between professional behaviors formally taught and what is witnessed has become increasingly evident. METHODS: With funding from the American Board of Internal Medicine Foundation, a workshop was developed to address unprofessional behaviors related to inpatient care previously identified in a multi-institution survey. The aims were to utilize video-based education to illustrate unprofessional behaviors, how faculty play a role in promoting such behaviors, and facilitate reflection regarding motivation for and prevention of these behaviors. Hospitalists and housestaff at 3 Chicago-area academic hospitals and 1 community teaching affiliate participated. Videos were debriefed, identifying barriers to professional behavior and improvement strategies. A postworkshop survey assessed beliefs on behaviors and intent to change practice. RESULTS: Forty-four (53%) faculty and 244 (68%) residents (postgraduate year 1 and greater) participated. The workshop was well received, with 89% reporting it "useful and effective." Two-thirds expressed intent to change behavior. Most (86%) believed videos were realistic and effective. Those who perceived videos as "very realistic" were more likely to report intent to change behavior (93% vs 53%, P = 0.01). CONCLUSIONS: Video-based education is a feasible way to promote reflection and address unprofessional behaviors among providers and may positively impact the learning environment.

Fatal spontaneous rectus sheath hematoma in a patient with cirrhosis.

Rectus sheath hematoma (RSH) is an uncommon and often misdiagnosed condition. This well-described entity is typically self-limited. In rare cases, the condition may be fatal. We report a case of a patient with cirrhosis who died of progressive RSH and its subsequent complications.

Structure and transcription of the human m3 muscarinic receptor gene.

We have isolated and characterized the human m3 muscarinic receptor gene and its promoter. Using 5' rapid amplification of cDNA ends (RACE), internal polymerase chain reaction (PCR), and homology searching to identify EST clones, we determined that the cDNA encoding the m3 receptor comprises 4,559 bp in 8 exons, which are alternatively spliced to exclude exons 2, 4, 6, and/or 7; the receptor coding sequence occurs within exon 8. Analysis of P1 artificial chromosome (PAC) and bacterial artificial chromosome (BAC) clones and of PCR- amplified genomic DNA, and homology searching of human chromosome 1 sequence provided from the Sanger Centre (Hinxton, Cambridge, UK) revealed that the m3 muscarinic receptor gene spans at least 285 kb. A promoter fragment containing bp -1240 to +101 (relative to the most 5' transcription start site) exhibited considerable transcriptional activity during transient transfection in cultured subconfluent, serum-fed canine tracheal myocytes, and 5' deletion analysis of promoter function revealed the presence of positive transcriptional regulatory elements between bp -526 and -269. Sequence analysis disclosed three potential AP-2 binding sites in this region; five more AP-2 consensus binding motifs occur between bp -269 and +101. Cotransfection with a plasmid expressing human AP-2alpha substantially increased transcription from m3 receptor promoter constructs containing 526 or 269 bp of 5' flanking DNA. Furthermore, m3 receptor promoter activity was enhanced by long-term serum deprivation of canine tracheal myocytes, a treatment that is known to increase AP-2 transcription-promoting activity in these cells. Together, these data suggest that expression of the human m3 muscarinic receptor gene is regulated in part by AP-2 in airway smooth muscle.

The RhoA/Rho kinase pathway regulates nuclear localization of serum response factor.

RhoA and its downstream target Rho kinase regulate serum response factor (SRF)-dependent skeletal and smooth muscle gene expression. We previously reported that long-term serum deprivation reduces transcription of smooth muscle contractile apparatus encoding genes, by redistributing SRF out of the nucleus. Because serum components stimulate RhoA activity, these observations suggest the hypothesis that the RhoA/Rho kinase pathway regulates SRF-dependent smooth muscle gene transcription in part by controlling SRF subcellular localization. Our present results support this hypothesis: cotransfection of cultured airway myocytes with a plasmid expressing constitutively active RhoAV14 selectively enhanced transcription from the SM22 and smooth muscle myosin heavy chain promoters and from a purely SRF-dependent promoter, but had no effect on transcription from the MSV-LTR promoter or from an AP2-dependent promoter. Conversely, inhibition of the RhoA/Rho kinase pathway by cotransfection with a plasmid expressing dominant negative RhoAN19, by cotransfection with a plasmid expressing Clostridial C3 toxin, or by incubation with the Rho kinase inhibitor, Y-27632, all selectively reduced SRF-dependent smooth muscle promoter activity. Furthermore, treatment with Y-27632 selectively reduced binding of SRF from nuclear extracts to its consensus DNA target, selectively reduced nuclear SRF protein content, and partially redistributed SRF from nucleus to cytoplasm, as revealed by quantitative immunocytochemistry. Treatment of cultured airway myocytes with latrunculin B, which reduces actin polymerization, also caused partial redistribution of SRF into the cytoplasm. Together, these results demonstrate for the first time that the RhoA/Rho kinase pathway controls smooth muscle gene transcription in differentiated smooth muscle cells, in part by regulating the subcellular localization of SRF. It is conceivable that the RhoA/Rho kinase pathway influences SRF localization through its effect on actin polymerization dynamics.