Results from randomized trial of pirfenidone in patients with chronic rejection (STOP-CLAD study).

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading long-term cause of poor outcomes after transplant and manifests by fibrotic remodeling of small airways and/or pleuroparenchymal fibroelastosis. This study evaluated the effect of pirfenidone on quantitative radiographic and pulmonary function assessment in patients with CLAD. METHODS: We performed a single-center, 6-month, randomized, placebo-controlled trial of pirfenidone in patients with CLAD. Randomization was stratified by CLAD phenotype. The primary outcome for this study was change in radiographic assessment of small airways disease, quantified as percentage of lung volume using parametric response mapping analysis of computed tomography scans (PRMfSAD); secondary outcomes included change in forced expiratory volume in 1 second (FEV1), change in forced vital capacity (FVC), and change in radiographic quantification of parenchymal disease (PRMPD). Linear mixed models were used to evaluate the treatment effect on outcome measures. RESULTS: The goal enrollment of 60 patients was not met due to the coronavirus disease of 2019 pandemic, with 23 patients included in the analysis. There was no significant difference over the study period between the pirfenidone vs placebo groups with regards to the observed change in PRMfSAD (+4.2% vs -0.4%; p = 0.22), FEV1 (-3.5% vs -3.6%; p = 0.97), FVC (-1.9% vs -4.6%; p = 0.41), or PRMPD (-0.6% vs -2.5%; p = 0.30). The study treatment tolerance and adverse events were generally similar between the pirfenidone and placebo groups. CONCLUSIONS: Pirfenidone had no apparent impact on radiographic evidence of allograft dysfunction or pulmonary function decline in a single-center randomized trial of CLAD patients that did not meet enrollment goals but had an acceptable tolerance and side-effect profile.

A multidimensional classifier to support lung transplant referral in patients with pulmonary fibrosis.

BACKGROUND: Lung transplantation remains the sole curative option for patients with idiopathic pulmonary fibrosis (IPF), but donor organs remain scarce, and many eligible patients die before transplant. Tools to optimize the timing of transplant referrals are urgently needed. METHODS: Least absolute shrinkage and selection operator was applied to clinical and proteomic data generated as part of a prospective cohort study of interstitial lung disease (ILD) to derive clinical, proteomic, and multidimensional logit models of near-term death or lung transplant within 18 months of blood draw. Model-fitted values were dichotomized at the point of maximal sensitivity and specificity, and decision curve analysis was used to select the best-performing classifier. We then applied this classifier to independent IPF and non-IPF ILD cohorts to determine test performance characteristics. Cohorts were restricted to patients aged ≤72 years with body mass index 18 to 32 to increase the likelihood of transplant eligibility. RESULTS: IPF derivation, IPF validation, and non-IPF ILD validation cohorts consisted of 314, 105, and 295 patients, respectively. A multidimensional model comprising 2 clinical variables and 20 proteins outperformed stand-alone clinical and proteomic models. Following dichotomization, the multidimensional classifier predicted near-term outcome with 70% sensitivity and 92% specificity in the IPF validation cohort and 70% sensitivity and 80% specificity in the non-IPF ILD validation cohort. CONCLUSIONS: A multidimensional classifier of near-term outcomes accurately discriminated this end-point with good test performance across independent IPF and non-IPF ILD cohorts. These findings support refinement and prospective validation of this classifier in transplant-eligible individuals.

The Lung Microbiome Predicts Mortality and Response to Azithromycin in Lung Transplant Recipients with Chronic Rejection.

Rationale: Chronic lung allograft dysfunction (CLAD) is the leading cause of death after lung transplant, and azithromycin has variable efficacy in CLAD. The lung microbiome is a risk factor for developing CLAD, but the relationship between lung dysbiosis, pulmonary inflammation, and allograft dysfunction remains poorly understood. Whether lung microbiota predict outcomes or modify treatment response after CLAD is unknown. Objectives: To determine whether lung microbiota predict post-CLAD outcomes and clinical response to azithromycin. Methods: Retrospective cohort study using acellular BAL fluid prospectively collected from recipients of lung transplant within 90 days of CLAD onset. Lung microbiota were characterized using 16S rRNA gene sequencing and droplet digital PCR. In two additional cohorts, causal relationships of dysbiosis and inflammation were evaluated by comparing lung microbiota with CLAD-associated cytokines and measuring ex vivo P. aeruginosa growth in sterilized BAL fluid. Measurements and Main Results: Patients with higher bacterial burden had shorter post-CLAD survival, independent of CLAD phenotype, azithromycin treatment, and relevant covariates. Azithromycin treatment improved survival in patients with high bacterial burden but had negligible impact on patients with low or moderate burden. Lung bacterial burden was positively associated with CLAD-associated cytokines, and ex vivo growth of P. aeruginosa was augmented in BAL fluid from transplant recipients with CLAD. Conclusions: In recipients of lung transplants with chronic rejection, increased lung bacterial burden is an independent risk factor for mortality and predicts clinical response to azithromycin. Lung bacterial dysbiosis is associated with alveolar inflammation and may be promoted by underlying lung allograft dysfunction.

Genetic deficiency of the transcription factor NFAT1 confers protection against fibrogenic responses independent of immune influx.

Idiopathic pulmonary fibrosis (IPF) is marked by unremitting matrix deposition and architectural distortion. Multiple profibrotic pathways contribute to the persistent activation of mesenchymal cells (MCs) in fibrosis, highlighting the need to identify and target common signaling pathways. The transcription factor nuclear factor of activated T cells 1 (NFAT1) lies downstream of second messenger calcium signaling and has been recently shown to regulate key profibrotic mediator autotaxin (ATX) in lung MCs. Herein, we investigate the role of NFAT1 in regulating fibroproliferative responses during the development of lung fibrosis. Nfat1-/--deficient mice subjected to bleomycin injury demonstrated improved survival and protection from lung fibrosis and collagen deposition as compared with bleomycin-injured wild-type (WT) mice. Chimera mice, generated by reconstituting bone marrow cells from WT or Nfat1-/- mice into irradiated WT mice (WT→WT and Nfat1-/-→WT), demonstrated no difference in bleomycin-induced fibrosis, suggesting immune influx-independent fibroprotection in Nfat1-/- mice. Examination of lung tissue and flow sorted lineageneg/platelet-derived growth factor receptor alpha (PDGFRα)pos MCs demonstrated decreased MC numbers, proliferation [↓ cyclin D1 and 5-ethynyl-2'-deoxyuridine (EdU) incorporation], myofibroblast differentiation [↓ α-smooth muscle actin (α-SMA)], and survival (↓ Birc5) in Nfat1-/- mice. Nfat1 deficiency abrogated ATX expression in response to bleomycin in vivo and MCs derived from Nfat1-/- mice demonstrated decreased ATX expression and migration in vitro. Human IPF MCs demonstrated constitutive NFAT1 activation, and regulation of ATX in these cells by NFAT1 was confirmed using pharmacological and genetic inhibition. Our findings identify NFAT1 as a critical mediator of profibrotic processes, contributing to dysregulated lung remodeling and suggest its targeting in MCs as a potential therapeutic strategy in IPF.NEW & NOTEWORTHY Idiopathic pulmonary fibrosis (IPF) is a fatal disease with hallmarks of fibroblastic foci and exuberant matrix deposition, unknown etiology, and ineffective therapies. Several profibrotic/proinflammatory pathways are implicated in accelerating tissue remodeling toward a honeycombed end-stage disease. NFAT1 is a transcriptional factor activated in IPF tissues. Nfat1-deficient mice subjected to chronic injury are protected against fibrosis independent of immune influxes, with suppression of profibrotic mesenchymal phenotypes including proliferation, differentiation, resistance to apoptosis, and autotaxin-related migration.

The intersection of race and ethnicity, gender, and primary diagnosis on lung transplantation outcomes.

BACKGROUND: Reducing racial disparities in lung transplant outcomes is a current priority of providers, policymakers, and lung transplant centers. It is unknown how the combined effect of race and ethnicity, gender, and diagnosis group is associated with differences in 1-year mortality and 5-year survival. METHODS: This is a longitudinal cohort study using Standard Transplant Analysis Research files from the United Network for organ sharing. A total of 25,444 patients undergoing first time lung transplantation between 2006 and 2019 in the United States. The primary exposures were lung transplant recipient race and ethnicity, gender, and primary diagnosis group at listing. Multivariable regression models and cox-proportional hazards models were used to determine adjusted 1-year mortality and 5-year survival. RESULTS: Overall, 25,444 lung transplant patients were included in the cohort including 15,160 (59.6%) men, 21,345 (83.9%) White, 2,318 (9.1%), Black and Hispanic/Latino (7.0%). Overall, men had a significant higher 1-year mortality than women (11.87%; 95% CI 11.07-12.67 vs 12.82%; 95% CI 12.20%-13.44%). Black women had the highest mortality of all race and gender combinations (14.51%; 95% CI 12.15%-16.87%). Black patients with pulmonary vascular disease had the highest 1-year mortality (19.77%; 95% CI 12.46%-27.08%) while Hispanic/Latino patients with obstructive lung disease had the lowest (7.42%; 95% CI 2.8%-12.05%). 5-year adjusted survival was highest among Hispanic/Latino patients (62.32%) compared to Black (57.59%) and White patients (57.82%). CONCLUSIONS: There are significant differences in 1-year and 5-year mortality between and within racial and ethnic groups depending on gender and primary diagnosis. This demonstrates the impact of social and clinical factors on lung transplant outcomes.

The mitigating effect of exogenous carbon monoxide on chronic allograft rejection and fibrosis post-lung transplantation.

BACKGROUND: Small airway inflammation and fibrosis or bronchiolitis obliterans (BO) is the predominant presentation of chronic lung allograft dysfunction (CLAD) post-lung transplantation. Carbon monoxide (CO) is a critical endogenous signaling transducer with known anti-inflammatory and anti-fibrotic effects but its therapeutic potential in CLAD remains to be fully elucidated. METHODS: Here we investigate the effect of inhaled CO in modulating chronic lung allograft rejection pathology in a murine orthotopic lung transplant model of BO (B6D2F1/J→DBA/2J). Additionally, the effects of CO on the activated phenotype of mesenchymal cells isolated from human lung transplant recipients with CLAD were studied. RESULTS: Murine lung allografts treated with CO (250 ppm × 30 minutes twice daily from days 7 to 40 post-transplantation) demonstrated decreased immune cell infiltration, fibrosis, and airway obliteration by flow cytometry, trichrome staining, and morphometric analysis, respectively. Decreased total collagen, with levels comparable to isografts, was noted in CO-treated allografts by quantitative hydroxyproline assay. In vitro, CO (250 ppm × 16h) was effective in reversing the fibrotic phenotype of human CLAD mesenchymal cells with decreased collagen I and ß-catenin expression as well as an inhibitory effect on ERK1/2 MAPK, and mTORC1/2 signaling. Sildenafil, a phosphodiesterase 5 inhibitor, partially mimicked the effects of CO on CLAD mesenchymal cells and was partially effective in decreasing collagen deposition in murine allografts, suggesting the contribution of cGMP-dependent and -independent mechanisms in mediating the effect of CO. CONCLUSION: These results suggest a potential role for CO in alleviating allograft fibrosis and mitigating chronic rejection pathology post-lung transplant.

A 30-Year-Old Immune Deficient Woman With Persistent Cough and Shortness of Breath.

CASE PRESENTATION: A 30-year-old woman was referred with increasing shortness of breath and cough in the setting of GATA2 deficiency. She initially presented 9 years previously with recurrent episodes of pneumonia and sinusitis. Genetic testing revealed a heterozygous GATA2 mutation (c.988C>T). She has since had multiple infections that have included necrotizing fasciitis of the right thumb, recurrent pilonidal infections (which required 23 procedures), esophageal candidiasis, and human papillomavirus-positive high-grade squamous intraepithelial lesion of the cervix. Serial bone marrow biopsy specimens showed persistent hypocellularity (20% to 60%) with intermittent erythroid atypia and variable detection of trisomy 8, which were concerning for evolving myelodysplastic syndrome. One year before the current admission, she was diagnosed with disseminated Mycobacterium avium complex and was treated with rifabutin, ethambutol, and azithromycin. She was taking voriconazole, acyclovir, and trimethoprim-sulfamethoxazole prophylaxis.

Radiographic Graft Surveillance in Lung Transplantation: Prognostic Role of Parametric Response Mapping.

Rationale: Chronic lung allograft dysfunction (CLAD) results in significant morbidity after lung transplantation. Potential CLAD occurs when lung function declines to 80-90% of baseline. Better noninvasive tools to prognosticate at potential CLAD are needed. Objectives: To determine whether parametric response mapping (PRM), a computed tomography (CT) voxel-wise methodology applied to high-resolution CT scans, can identify patients at risk of progression to CLAD or death. Methods: Radiographic features and PRM-based CT metrics quantifying functional small airway disease (PRMfSAD) and parenchymal disease (PRMPD) were studied at potential CLAD (n = 61). High PRMfSAD and high PRMPD were defined as ⩾30%. Restricted mean modeling was performed to compare CLAD-free survival among groups. Measurements and Main Results: PRM metrics identified the following three unique signatures: high PRMfSAD (11.5%), high PRMPD (41%), and neither (PRMNormal; 47.5%). Patients with high PRMfSAD or PRMPD had shorter CLAD-free median survival times (0.46 yr and 0.50 yr) compared with patients with predominantly PRMNormal (2.03 yr; P = 0.004 and P = 0.007 compared with PRMfSAD and PRMPD groups, respectively). In multivariate modeling adjusting for single- versus double-lung transplant, age at transplant, body mass index at potential CLAD, and time from transplant to CT scan, PRMfSAD ⩾30% or PRMPD ⩾30% continue to be statistically significant predictors of shorter CLAD-free survival. Air trapping by radiologist interpretation was common (66%), was similar across PRM groups, and was not predictive of CLAD-free survival. Ground-glass opacities by radiologist read occurred in 16% of cases and were associated with decreased CLAD-free survival (P < 0.001). Conclusions: PRM analysis offers valuable prognostic information at potential CLAD, identifying patients most at risk of developing CLAD or death.

Lung microbiota predict chronic rejection in healthy lung transplant recipients: a prospective cohort study.

BACKGROUND: Alterations in the respiratory microbiome are common in chronic lung diseases, correlate with decreased lung function, and have been associated with disease progression. The clinical significance of changes in the respiratory microbiome after lung transplant, specifically those related to development of chronic lung allograft dysfunction (CLAD), are unknown. The aim of this study was to evaluate the effect of lung microbiome characteristics in healthy lung transplant recipients on subsequent CLAD-free survival. METHODS: We prospectively studied a cohort of lung transplant recipients at the University of Michigan (Ann Arbor, MI, USA). We analysed characteristics of the respiratory microbiome in acellular bronchoalveolar lavage fluid (BALF) collected from asymptomatic patients during per-protocol surveillance bronchoscopy 1 year after lung transplantation. For our primary endpoint, we evaluated a composite of development of CLAD or death at 500 days after the 1-year surveillance bronchoscopy. Our primary microbiome predictor variables were bacterial DNA burden (total 16S rRNA gene copies per mL of BALF, quantified via droplet digital PCR) and bacterial community composition (determined by bacterial 16S rRNA gene sequencing). Patients' lung function was followed serially at least every 3 months by spirometry, and CLAD was diagnosed according to International Society of Heart and Lung Transplant 2019 guidelines. FINDINGS: We analysed BALF from 134 patients, collected during 1-year post-transplant surveillance bronchoscopy between Oct 21, 2005, and Aug 25, 2017. Within 500 days of follow-up from the time of BALF sampling, 24 (18%) patients developed CLAD, five (4%) died before confirmed development of CLAD, and 105 (78%) patients remained CLAD-free with complete follow-up. Lung bacterial burden was predictive of CLAD development or death within 500 days of the surveillance bronchoscopy, after controlling for demographic and clinical factors, including immunosuppression and bacterial culture results, in a multivariable survival model. This relationship was evident when burden was analysed as a continuous variable (per log10 increase in burden, HR 2·49 [95% CI 1·38-4·48], p=0·0024) or by tertiles (middle vs lowest bacterial burden tertile, HR 4·94 [1·25-19·42], p=0·022; and highest vs lowest, HR 10·56 [2·53-44·08], p=0·0012). In patients who developed CLAD or died, composition of the lung bacterial community significantly differed to that in patients who survived and remained CLAD-free (on permutational multivariate analysis of variance, p=0·047 at the taxonomic level of family), although differences in community composition were associated with bacterial burden. No individual bacterial taxa were definitively associated with CLAD development or death. INTERPRETATION: Among asymptomatic lung transplant recipients at 1-year post-transplant, increased lung bacterial burden is predictive of chronic rejection and death. The lung microbiome represents an understudied and potentially modifiable risk factor for lung allograft dysfunction. FUNDING: US National Institutes of Health, Cystic Fibrosis Foundation, Brian and Mary Campbell and Elizabeth Campbell Carr research gift fund.

COVID-19 Outcomes Among Solid Organ Transplant Recipients: A Case-control Study.

BACKGROUND: Solid organ transplant (SOT) recipients are considered to be "vulnerable" to COVID-19 infection due to immunosuppression. To date, there are no studies that compared the disease severity of COVID-19 in SOT recipients with nontransplant patients. METHODS: In this case-control study, we compared the outcomes of COVID-19 between SOT recipients and their matched nontransplant controls. The cases were all adult SOT recipients (N = 41) from our academic health center who were diagnosed with COVID-19 between March 10, 2020 and May 15, 2020 using positive reverse transcriptase polymerase chain reaction for SARS-CoV2. The controls (N = 121) were matched on age (±5 y), race, and admission status (hospital or outpatient). The primary outcome was death and secondary outcomes were severe disease, intubation and renal replacement therapy (RRT). RESULTS: Median age of SOT recipients (9 heart, 3 lung, 16 kidney, 8 liver, and 5 dual organ) was 60 y, 80% were male and 67% were Black. Severe disease adjusted risk of death was similar in both the groups (hazard ratio = 0.84 [0.32-2.20]). Severity of COVID-19 and intubation were similar, but the RRT use was higher in SOT (odds ratio = 5.32 [1.26, 22.42]) compared to non-SOT COVID-19 patients. Among SOT recipients, COVID-19-related treatment with hydroxychloroquine (HCQ) was associated with 10-fold higher hazard of death compared to without HCQ (hazard ratio = 10.62 [1.24-91.09]). CONCLUSIONS: Although African Americans constituted one-tenth of all SOT in our center, they represented two-thirds of COVID-19 cases. Despite high RRT use in SOT recipients, the severe disease and short-term death were similar in both groups. HCQ for the treatment of COVID-19 among SOT recipients was associated with high mortality and therefore, its role as a treatment modality requires further scrutiny.

Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.

Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3 Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.

Humoral immune responses mediate the development of a restrictive phenotype of chronic lung allograft dysfunction.

Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 → parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human RAS lungs. Gene expression profiling revealed differential humoral immune cell activation as a key feature of the RAS murine model, with significant B cell and plasma cell infiltration noted in the RAS lung allografts. B6D2F1/J lung allografts transplanted into µMt-/- (mature B cell deficient) or activation-induced cytidine deaminase (AID)/secretory µ-chain (µs) double-KO (AID-/-µs-/-) C57BL/6J mice demonstrated significantly decreased allograft fibrosis, indicating a key role for antibody secretion by B cells in mediating RAS pathology. Our study suggests that skewing of immune responses determines the diverse allograft remodeling patterns and highlights the need to develop targeted therapies for specific CLAD phenotypes.

Fibroproliferation in chronic lung allograft dysfunction: Association of mesenchymal cells in bronchoalveolar lavage with phenotypes and survival.

BACKGROUND: Chronic lung allograft dysfunction (CLAD), the primary cause of poor outcome after lung transplantation, arises from fibrotic remodeling of the allograft and presents as diverse clinical phenotypes with variable courses. Here, we investigate whether bronchoalveolar lavage (BAL) mesenchymal cell activity at CLAD onset can inform regarding disease phenotype, progression, and survival. METHODS: Mesenchymal cell colony-forming units (CFUs) were measured in BAL obtained at CLAD onset (n = 77) and CLAD-free time post-transplant matched controls (n = 77). CFU counts were compared using Wilcoxon's rank-sum test. Cox proportional hazards and restricted means models were utilized to investigate post-CLAD survival. RESULTS: Higher mesenchymal CFU counts were noted in BAL at the time of CLAD onset than in CLAD-free controls. Patients with restrictive allograft syndrome had higher BAL mesenchymal CFU count at CLAD onset than patients with bronchiolitis obliterans syndrome (p = 0.011). Patients with high mesenchymal CFU counts (≥10) at CLAD onset had worse outcomes than those with low (<10) CFU counts, with shorter average survival (2.64 years vs 4.25 years; p = 0.027) and shorter progression-free survival, defined as time to developing either CLAD Stage 3 or death (0.97 years vs 2.70 years; p < 0.001). High CFU count remained predictive of decreased overall survival and progression-free survival after accounting for the CLAD phenotype and other clinical factors in multivariable analysis. CONCLUSIONS: Fulminant fibroproliferation with higher mesenchymal CFU counts in BAL is noted in restrictive allograft syndrome and is independently associated with poor survival after CLAD onset.

The association of sleep quality, delirium, and sedation status with daily participation in physical therapy in the ICU.

BACKGROUND: Poor sleep is common in the ICU setting and may represent a modifiable risk factor for patient participation in ICU-based physical therapy (PT) interventions. This study evaluates the association of perceived sleep quality, delirium, sedation, and other clinically important patient and ICU factors with participation in physical therapy (PT) interventions. METHOD: This was a secondary analysis of a prospective observational study of sleep in a single academic medical ICU (MICU). Perceived sleep quality was assessed using the Richards-Campbell Sleep Questionnaire (RCSQ) and delirium was assessed using the Confusion Assessment Method for the ICU (CAM-ICU). Other covariates included demographics, pre-hospitalization ambulation status, ICU admission diagnosis, daily mechanical ventilation status, and daily administration of benzodiazepines and opioids via bolus and continuous infusion. Associations with participation in PT interventions were assessed among patients eligible for PT using a multinomial Markov model with robust variance estimates. RESULTS: Overall, 327 consecutive MICU patients completed ≥1 assessment of perceived sleep quality. After adjusting for all covariates, daily assessment of perceived sleep quality was not associated with transitioning to participate in PT the following day (relative risk ratio [RRR] 1.02, 95 % CI 0.96-1.07, p = 0.55). However, the following factors had significant negative associations with participating in subsequent PT interventions: delirium (RRR 0.58, 95 % CI 0.41-0.76, p <0.001), opioid boluses (RRR 0.68, 95 % CI 0.47-0.99, p = 0.04), and continuous sedation infusions (RRR 0.58, 95 % CI 0.40-0.85, p = 0.01). Additionally, in patients with delirium, benzodiazepine boluses further reduced participation in subsequent PT interventions (RRR 0.25, 95 % CI 0.13-0.50, p <0.001). CONCLUSIONS: Perceived sleep quality was not associated with participation in PT interventions the following day. However, continuous sedation infusions, opioid boluses, and delirium, particularly when occurring with administration of benzodiazepine boluses, were negatively associated with subsequent PT interventions and represent important modifiable factors for increasing participation in ICU-based PT interventions.

Substituted judgment in principle and practice: a national physician survey.

OBJECTIVE: To describe the extent to which US physicians endorse substituted judgments in principle or accommodate them in practice. PATIENTS AND METHODS: We surveyed a stratified, random sample of 2016 physicians by mail from June 25, 2010, to September 3, 2010. Primary outcome measures were agreement with 2 in-principle statements about substituted judgment and, after an experimental vignette that varied the basis used by a patient's surrogate to refuse life-saving treatment, responses indicating how appropriate it would be to overrule the surrogate's decision. RESULTS: Our response rate was 62% (1156 of 1875 respondents). When there is a conflict between what a surrogate believes a patient would have wanted (substituted judgment) and what the surrogate believes is in the patient's best interest, 4 of 5 physicians (78%) agreed that the surrogate should base their decision on substituted judgment. Yet we also found that 2 of 5 physicians (40%) agree that surrogates should make decisions they believe are in the patient's best interest, even if those seem to contradict the patient's prior wishes. In the experimental vignette, physicians were much more likely to oppose overruling a surrogate's refusal of life-sustaining medical treatment when that refusal was made on the basis of substituted judgment compared with when the refusal was made on the basis of the patient's best interest (50% vs 20%; odds ratio, 4.2; 95% CI, 2.7-6.3). Responses to the in-principle items about substituted judgment were not consistently associated with responses to the experimental vignette. CONCLUSION: US physicians largely agree, in principle, that surrogates should prioritize what the patient would have wanted over what they believe is in the patient's best interest, although many physicians are ambivalent in cases in which the 2 norms conflict. Even physicians who reject the principle of substituted judgment tend to treat substituted judgment as the preferred norm for surrogate decision making when responding to a clinical vignette.

Conscientious refusals to refer: findings from a national physician survey.

BACKGROUND: Regarding controversial medical services, many have argued that if physicians cannot in good conscience provide a legal medical intervention for which a patient is a candidate, they should refer the requesting patient to an accommodating provider. This study examines what US physicians think a doctor is obligated to do when the doctor thinks it would be immoral to provide a referral. METHOD: The authors conducted a cross-sectional survey of a random sample of 2000 US physicians from all specialties. The primary criterion variable was agreement that physicians have a professional obligation to refer patients for all legal medical services for which the patients are candidates, even if the physician believes that such a referral is immoral. RESULTS: Of 1895 eligible physicians, 1032 (55%) responded. 57% of physicians agreed that doctors must refer patients regardless of whether or not the doctor believes the referral itself is immoral. Holding this opinion was independently associated with being more theologically pluralistic, describing oneself as sociopolitically liberal, and indicating that respect for patient autonomy is the most important bioethical principle in one's practice (multivariable ORs, 1.6-2.4). CONCLUSIONS: Physicians are divided about a professional obligation to refer when the physician believes that referral itself is immoral. These data suggest there is no uncontroversial way to resolve conflicts posed when patients request interventions that their physicians cannot in good conscience provide.

Blacks, whites, and attitudes towards abortion.

PIP: Patterns of black and white support for abortion from 1972-80 in the US were examined in order to investigate the significance of race in attitudes toward abortion, analyze the extent to which other factors such as religious practice (religiosity) and demographic characteristics affect these racial differences; and determine what changes, if any, occurred in the salience of race on abortion attitudes during this 9-year period. The General Social Survey (GSS) conducted from 1972-80 were used. These surveys, done annually with the exception of 1979, use national samples of approximately 1500 respondents each year. A modified probability sampling design was used in 1972 through 1974, full probability sampling in 1977-80, and a combination of the 2 in 1975 and 1976. 6 standard questions tapping abortion attitudes were asked in each of these surveys. From these 6 items an additive scale was created, with values ranging from 0, when abortion was opposed in every case, to 6, where approval was given for abortion in each case. This scale was used as a dependent variable in the analyses. There was a great deal of public stability in public attitudes toward abortion. This was particularly the case for the health, rape, and birth defect items, where little change was evident in either race, except for increased black support for abortion when the mother's health is threatened. For the other items, support by blacks appears to have increased during this time, while support by whites dropped slightly. The amount of convergence was not statistically significant. Blacks remained significantly less likely to favor abortion in all 6 instances, they were, by 1978-80, almost equally unlikely to oppose abortion in all cases (9% for whites, 12% for blacks). The mean number of abortion items supported by blacks increased from 3.1 in 1972-74 to 3.3 in 1978-80; white support dropped from 4.0 to 3.9 in 1978-80 (though returning to 4.0 in 1980). Much of the difference in support of abortion, though not all, was due to the different demographic characteristics of blacks and whites, and the greater degree of religiosity of blacks. Most of the factors hypothesized to affect black attitudes appeared to do so: education; income; urban and northern residence; and lesser religiosity where each related to greater support for abortion. There was no direct evidence to support or refute the legitimacy of the "abortion as black genocide" argument, but the fact that opposition to abortion comes from the seemingly more traditional segment of the black community seems to provide some indirect evidence that the argument does not account for the greater black opposition to abortion.^ieng